Anti-Viral Compounds

ABSTRACT

Compounds effective in inhibiting replication of Hepatitis C virus (“HCV”) are described. This invention also relates to processes of making such compounds, compositions comprising such compounds, and methods of using such compounds to treat HCV infection.

The present application is a continuation-in-part of U.S. patentapplication Ser. No. 12/964,027, filed Dec. 9, 2010, which is acontinuation-in-part of U.S. patent application Ser. No. 12/903,822,filed Oct. 13, 2010, which is a continuation-in-part of U.S. patentapplication Ser. No. 12/813,301, filed Jun. 10, 2010, which claims thebenefit from U.S. Provisional Application Ser. No. 61/186,291, filedJun. 11, 2009, U.S. Provisional Application Ser. No. 61/242,836, filedSep. 16, 2009, and U.S. Provisional Application Ser. No. 61/243,596,filed Sep. 18, 2009; the present application also claims the benefitfrom U.S. Provisional Application Ser. No. 61/446,800, filed Feb. 25,2011. All of these applications are incorporated herein by reference intheir entireties.

FIELD

The present invention relates to compounds effective in inhibitingreplication of Hepatitis C virus (“HCV”). The present invention alsorelates to compositions comprising these compounds and methods of usingthese compounds to treat HCV infection.

BACKGROUND

HCV is an RNA virus belonging to the Hepacivirus genus in theFlaviviridae family. The enveloped HCV virion contains a positivestranded RNA genome encoding all known virus-specific proteins in asingle, uninterrupted, open reading frame. The open reading framecomprises approximately 9500 nucleotides and encodes a single largepolyprotein of about 3000 amino acids. The polyprotein comprises a coreprotein, envelope proteins E1 and E2, a membrane bound protein p7, andthe non-structural proteins NS2, NS3, NS4A, NS4B, NS5A and NS5B.

The nonstructural protein NS5A is a membrane-associated phosphoproteinpresent in basally phosphorylated and hyperphosphorylated forms. It is acritical component of HCV replication and is believed to exert multiplefunctions at various stages of the viral life cycle. A full-length NS5Aprotein comprises three domains—namely, Domain I, Domain II, and DomainIII. Domain I (residues 1 to 213) contains a zinc-binding motif and anamphipathic N-terminal helix which can promote membrane association.Domain II (residues 250 to 342) has regulatory functions, such asinteractions with protein kinase PKR and PI3K, as well as NS5B, and alsocontains the interferon sensitivity-determining region. Domain III(residues 356 to 447) plays a role in infectious virion assembly, andcan be modulated by phosphorylation within the domain. NS5A has beenidentified as a promising therapeutic target for treating HCV.

SUMMARY

The present invention features compounds of Formulae I, I_(A), I_(B),I_(C), I_(D), I_(E), I_(F) and I_(G) and pharmaceutically acceptablesalts thereof. These compounds and salts can inhibit the replication ofHCV and therefore are useful for treating HCV infection.

The present invention also features compositions comprising thecompounds or salts of the present invention. The compositions can alsoinclude additional therapeutic agents, such as HCV helicase inhibitors,HCV polymerase inhibitors, HCV protease inhibitors, HCV NS5A inhibitors,CD81 inhibitors, cyclophilin inhibitors, or internal ribosome entry site(IRES) inhibitors.

The present invention further features methods of using the compounds orsalts of the present invention to inhibit HCV replication. The methodscomprise contacting cells infected with HCV virus with a compound orsalt of the present invention, thereby inhibiting the replication of HCVvirus in the cells.

In addition, the present invention features methods of using thecompounds or salts of the present invention, or compositions comprisingthe same, to treat HCV infection. The methods comprise administering acompound or salt of the present invention, or a pharmaceuticalcomposition comprising the same, to a patient in need thereof, therebyreducing the blood or tissue level of HCV virus in the patient.

The present invention also features use of the compounds or salts of thepresent invention for the manufacture of medicaments for the treatmentof HCV infection.

Furthermore, the present invention features processes of making thecompounds or salts of the invention.

Other features, objects, and advantages of the present invention areapparent in the detailed description that follows. It should beunderstood, however, that the detailed description, while indicatingpreferred embodiments of the invention, are given by way of illustrationonly, not limitation. Various changes and modifications within the scopeof the invention will become apparent to those skilled in the art fromthe detailed description.

DETAILED DESCRIPTION

Tellinghuisen et al., NATURE 435:374-379 (2005), describes a crystalstructure of the NS5A protein in which two NS5A monomers are packed as adimer via contacts near the N-terminal ends of the molecules.WO2006093867 postulates the use of the crystal structure of the NS5Aprotein in conjunction of computer modeling to design or select NS5Ainhibitors.

To improve interactions with the NS5A protein, many NS5A inhibitors havebeen designed to have dimeric or dimer-like structures. For instance,WO2006133326 (BMS) describes compounds with the formula:

WO2008144380 (BMS) depicts compounds with the formula:

WO2008021927(BMS) shows compounds with the formula:

WO2008021927 (BMS) describes compounds with the formula:

and US20100068176 (BMS) shows compounds with the formula:

wherein L is selected from aryls (e.g.,

heteroaryls (e.g.,

aliphatic groups (e.g.,

or a combination thereof (e.g.,

Certain modifications to the above formulae have also been provided. Forinstance, WO2010065681 (Presidio) discloses the formula:

wherein B is Q or Q-Q, and each Q is independently selected fromcycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl, with theproviso that only one Q is a six member aromatic ring when B is Q-Q andwith the proviso that if B is Q-Q, any Q is that is polycyclic isconnected to the remainder of the molecule through only one cycle of thepolycycle; WO2010096777 (Presidio) describes a similar formula:

wherein B is W—W or W—X″—W, and wherein each W is optionally substitutedaryl or heteroaryl, and X″ is selected from —O—, —S(O)_(k), —N(R^(N))—and —CR′₂—; WO2010096462 (Enanta) and US20100266543 (Enanta) show theformula:

wherein A is optionally substituted aryl, heteroaryl, heterocyclic,C₃-C₈cycloalkyl or C₃-C₈cycloalkenyl; and US20100221215 (Enanta) depictsthe formula:

wherein A is selected from aryl, heteroaryl, heterocyclic,C₃-C₈cycloalkyl or C₃-C₈cycloalkenyl, each optionally substituted, D isabsent or an optionally substituted aliphatic group, T is absent or anoptionally substituted linear aliphatic group containing zero to eightcarbons, E is absent or independently selected from optionallysubstituted aryl and optionally substituted heteroaryl, and wherein oneor two of D, E, and T are absent.

Tables 1-4 compare the antiviral activities of different NS5A compounds.As demonstrated by these tables, several compounds that are genericallycovered by WO2010065681 (Presidio) WO2010096777 (Presidio), WO2010096462(Enanta), US20100266543 (Enanta), WO2010096462 (Enanta) andUS20100266543 (Enanta) appear to have comparable or worse anti-HCVactivities than the corresponding compounds described in the BMSapplications. WO2010065681 (Presidio) WO2010096777 (Presidio),WO2010096462 (Enanta), US20100266543 (Enanta), WO2010096462 (Enanta) andUS20100266543 (Enanta) also fail to identify any advantage of thesecompounds over those described in the BMS applications.

employs a biphenyl linker between the imidazole moieties. SeeWO2008021927(BMS). The EC₅₀ values of BMS-790052 against different HCVgenotypes were shown by Nettles et al., “BMS-790052 is a First-in-classPotent Hepatitis C Virus (HCV) NS5A Inhibitor for Patients with ChronicHCV Infection: Results from a Proof-of-concept Study”, 59th AnnualMeeting of the American Association for the Study of Liver Diseases(Oct. 31-Nov. 1, 2008, San Francisco, Calif.;www.natap.org/2008/AASLD/AASLD_(—)06.htm). Specifically, Nettles et al.,observed that the EC₅₀ values of BMS-790052 against HCV genotypes 1a 1b,3a, 4a and 5a were 0.05, 0.009, 0.127, 0.012, and 0.033 nM,respectively. See also Gao et al., NATURE 465:96-100 (2010). Thecompounds in Table 1 use different linkers between the imidazolemoieties. Table 1 depicts the EC₅₀ values of these compounds when testedusing respective replicon assays in the presence of 5% (v/v) fetalbovine serum (FBS). As compared to BMS-790052, the replacement of thebiphenyl linker with other linkers can significantly reduce thecompounds' activities against various HCV genotypes.

TABLE 1 Biphenyl linker versus other linkers EC₅₀ (nM) 1a 1b 2a 2b 3a 4a5a 6a

see Nettles et al., supra

0.12 0.03 16 0.09 1.5 0.03 0.05 0.5

0.71 0.06 9.0 0.4 2.3 0.04 0.08 0.5

>10 8.5 >100 >10 >10 4.0 >10 >10

Table 2 compares compounds containing unsubstituted benzimidazole tothose containing halo-substituted benzimidazole. Anti-viral activitieswere assessed using wild-type replicons (e.g., 1b WT or 1a WT) as wellas replicons containing specific NS5A mutations (e.g., 1b L28T, 1b Y93H,1a L31V, 1a Y93C, 1a M28V, or 1a Q30E) in the absence of FBS. Ascompared to the reference compound which contains unsubstitutedbenzimidazole, compounds containing substituted benzimidazole generallyexhibited comparable or worse activities against many of these HCVviruses.

TABLE 2 Unsubstituted benzimidazole versus halo-substitutedbenzimidazole EC₅₀ (nM) 1b 1b 1b 1a 1a 1a 1a 1a WT L28T Y93H WT L31VY93C M28V Q30E

0.01 2.7 0.9 0.09 36 40 1.0 40

0.003 1.8 0.5 0.14 109 26 2.4 119

0.004 4.3 2.4 0.26 5.5 34 1.8 59

0.005 >10 5.7 0.28 33 103 11.6 306

0.007 >10 3.6 0.1 80 141 5.8 52

The present invention surprisingly discovered that compounds withhalo-substituted benzimidazole (e.g.,

can have better activity against certain HCV variants containing NS5Amutations (e.g., 1a L31V). Similar testing also showed that

as compared to the reference compound in Table 2, exhibitedsignificantly improved activity against the HCV 1a variant containingthe NS5A mutation M28T. These improvements have not been described orsuggested in any of the above-mentioned BMS, Presidio or Enantaapplications. Accordingly, the present invention features methods ofusing the compounds containing halo-substituted benzimidazole (e.g.,

to treat HCV variants (e.g., 1a M28T or 1a L31V). These methods compriseadministering an effective amount of such a compound to a patientinfected with such a HCV variant (e.g., 1a M28T or 1a L31V).

It was also found that when the phenyl linker between the benzimidazolemoieties was replaced with a pyrrolidinyl link (e.g.,

the process chemistry to introduce halo substitutions to thebenzimidazole moieties became extremely difficult. The above-mentionedBMS, Presidio and Enanta applications do not provide any enabledisclosure that would allow halo substitutions on the benzimidazolemoieties in a compound in which the phenyl linker is replaced with

Scheme XXIV and various Example of the present application (e.g.,Examples 2.16, 3.35-3.41, 3.46-3.53, 4.26-4.31, 4.37-4.40, 4.42-4.46,and 4.51-4.57) provide an enabling disclosure that allows suchsubstitutions in compounds with substituted pyrrolidinyl linkers.

Table 3 compares compounds with different linkers between thebenzimidazole moieties. Anti-viral activities were determined using 1aand 1b replicon assays. “HP” refers to human plasma. The compoundcontaining the pyrrolidinyl linker showed significantly worse anti-HCVactivities than those containing the pyridinyl linker. As compared tothe phenyl linker

used in US20100068176 (BMS), the pyridinyl linker

or like 6-membered aromatic linkers are expected to provide similar orcomparable anti-HCV activities.

TABLE 3 Non-aromatic heterocyclic linker versus aromatic heterocycliclinker EC₅₀ (nM, EC₅₀ (nM, in the in the presence of presence of 5% FBS)5% FBS and 40% HP) 1a 1b 1a 1b

>250 >250 2500-8000 >4500

<0.32 <0.32 <3.2 <3.2

6.8 2.9 83 190

Table 4 further shows that when the phenyl linker is replaced with apyrrolidinyl linker, the compound's activity against HCV can besignificantly reduced. The compound in Table 4 contains a pyrrolidinyllinker and has EC₅₀ values of over 200 nM. In comparison, BMS-790052,which contains a biphenyl linker, has EC₅₀ values of no more than 0.2nM. see Nettles et al., supra. Therefore, Tables 3 and 4 clearlydemonstrate that the use of an unsubstituted pyrrolidinyl linker in adimeric or dimer-like NS5A inhibitor can lead to poor anti-HCVactivities.

TABLE 4 Non-aromatic heterocyclic linker versus aromatic heterocycliclinker EC₅₀ (nM, in the EC₅₀ (nM, in the presence presence of 5% FBS) of5% FBS and 40% HP) 1a 1b 1a 1b

290 320 1200 2400

The present invention unexpectedly discovered that when the nitrogenatom in the pyrrolidinyl linker is substituted with carbocycle orheterocycle, the anti-viral activities of the compound can bedrastically improved. Table 5 shows the anti-HCV activities of compoundsin which the pyrrolidinyl linker is substituted with substitutedcarbocycle or heterocycle.

TABLE 5 Substituted pyrrolidinyl linker EC₅₀ (nM, in the presence EC₅₀of 40% HP) (nM, in the absence of HP) 1a 1b 2a 2b 3a 4a

0.1 0.3 0.2 ≦0.05 ≦0.05 ≦0.05

0.1 0.3 ≦0.05 ≦0.05 ≦0.05 ≦0.05

0.3 0.8

0.2 0.4 ≦0.05 ≦0.05 ≦0.05 ≦0.05

0.1 0.2 ≦0.05 ≦0.05 ≦0.05 ≦0.05

0.2 0.2 ≦0.05 ≦0.05 ≦0.05 ≦0.05

0.6 0.3 0.5 ≦0.05 ≦0.05 ≦0.05

0.4 0.5 0.07 ≦0.05 ≦0.05 ≦0.05

0.1 0.2 ≦0.05 ≦0.05 ≦0.05 ≦0.05

0.1 0.1 ≦0.05 ≦0.05 ≦0.05 ≦0.05

0.5 0.6 ≦0.05 ≦0.05 ≦0.05 ≦0.05

0.1 0.2

1.5 1.5 0.5 0.5 0.5 0.2

0.1 0.2 ≦0.05 ≦0.05 ≦0.05 ≦0.05

0.2 0.1 ≦0.05 ≦0.05 ≦0.05 ≦0.05

It is noted that the anti-HCV activity of

has not been shown to be better than that of

Table 5 also demonstrates that additional halo substitution(s) on thecarbocycle/heterocycle substituents on the pyrrolidinyl linker cansignificantly improve the compounds' anti-HCV activities (e.g., compareExample 4.25 to Example 3.20 or Example 5.1).

The present invention features compounds having Formula I, andpharmaceutically acceptable salts thereof,

wherein:

-   -   X is C₃-C₁₂carbocycle or 3- to 12-membered heterocycle, and is        optionally substituted with one or more R_(A) or R_(F);    -   L₁ and L₂ are each independently selected from bond; or        C₁-C₆alkylene, C₂-C₆alkenylene or C₂-C₆alkynylene, each of which        is independently optionally substituted at each occurrence with        one or more R_(L);    -   L₃ is bond or -L_(S)-K-L_(S)′-, wherein K is selected from bond,        —O—, —S—, —N(R_(B))—, —C(O)—, —S(O)₂—, —S(O)—, —OS(O)—,        —OS(O)₂—, —S(O)₂O—, —S(O)O—, —C(O)O—, —OC(O)—, —OC(O)O—,        —C(O)N(R_(B))—, —N(R_(B))C(O)—, —N(R_(B))C(O)O—,        —OC(O)N(R_(B))—, —N(R_(B))S(O)—, —N(R_(B))S(O)₂—,        —S(O)N(R_(B))—, —S(O)₂N(R_(B))—, —C(O)N(R_(B))C(O)—,        —N(R_(B))C(O)N(R_(B)′)-, —N(R_(B))SO₂N(R_(B)′)-, or        —N(R_(B))S(O)N(R_(B)′)-;    -   A and B are each independently C₃-C₁₂carbocycle or 3- to        12-membered heterocycle, and are each independently optionally        substituted with one or more R_(A);    -   D is C₃-C₁₂carbocycle or 3- to 12-membered heterocycle, and is        optionally substituted with one or more R_(A); or D is        C₃-C₁₂carbocycle or 3- to 12-membered heterocycle which is        substituted with J and optionally substituted with one or more        R_(A), where J is C₃-C₁₂carbocycle or 3- to 12-membered        heterocycle and is optionally substituted with one or more        R_(A), or J is —SF₅; or D is hydrogen or R_(A);    -   Y is selected from -T′—C(R₁R₂)N(R₅)-T-R_(D),        -T′—C(R₃R₄)C(R₆R₇)-T-R_(D), -L_(K)-T-R_(D), or -L_(K)-E;    -   R₁ and R₂ are each independently R_(C), and R₅ is R_(B); or R₁        is R_(C), and R₂ and R₅, taken together with the atoms to which        they are attached, form a 3- to 12-membered heterocycle which is        optionally substituted with one or more R_(A);    -   R₃, R₄, R₆, and R₇ are each independently R_(C); or R₃ and R₆        are each independently R_(C), and R₄ and R₇, taken together with        the atoms to which they are attached, form a 3- to 12-membered        carbocycle or heterocycle which is optionally substituted with        one or more R_(A);    -   Z is selected from -T′—C(R₈R₉)N(R₁₂)-T-R_(D),        -T′—C(R₁₀R₁₁)C(R₁₃R₁₄)-T-R_(D), -L_(K)-T-R_(D), or -L_(K)-E;    -   R₈ and R₉ are each independently R_(C), and R₁₂ is R_(B); or R₈        is R_(C), and R₉ and R₁₂, taken together with the atoms to which        they are attached, form a 3- to 12-membered heterocycle which is        optionally substituted with one or more R_(A);    -   R₁₀, R₁₁, R₁₃, and R₁₄ are each independently R_(C); or R₁₀ and        R₁₃ are each independently R_(C), and R₁₁ and R₁₄, taken        together with the atoms to which they are attached, form a 3- to        12-membered carbocycle or heterocycle which is optionally        substituted with one or more R_(A);    -   T and T′ are each independently selected at each occurrence from        bond, -L_(S)-, -L_(S)-M-L_(S)′-, or -L_(S)-M-L_(S)′-M′-L_(S)″—,        wherein M and M′ are each independently selected at each        occurrence from bond, —O—, —S—, —N(R_(B))—, —C(O)—, —S(O)₂—,        —S(O)—, —OS(O)—, —OS(O)₂—, —S(O)₂O—, —S(O)O—, —C(O)O—, —OC(O)—,        —OC(O)O—, —C(O)N(R_(B))—, —N(R_(B))C(O)—, —N(R_(B))C(O)O—,        —OC(O)N(R_(B))—, —N(R_(B))S(O)—, —N(R_(B))S(O)₂—,        —S(O)N(R_(B))—, —S(O)₂N(R_(B))—, —C(O)N(R_(B))C(O)—,        —N(R_(B))C(O)N(R_(B)′)-, —N(R_(B))SO₂N(R₁₃′)-,        —N(R_(B))S(O)N(R_(B)′)-, C₃-C₁₂carbocycle or 3- to 12-membered        heterocycle, and wherein said C₃-C₁₂carbocycle and 3- to        12-membered heterocycle are each independently optionally        substituted at each occurrence with one or more R_(A);    -   L_(K) is independently selected at each occurrence from bond,        -L_(S)-N(R_(B))C(O)-L_(S)′- or -L_(S)-C(O)N(R_(B))-L_(S)′-; or        C₁-C₆alkylene, C₂-C₆alkenylene or C₂-C₆alkynylene, each of which        is independently optionally substituted at each occurrence with        one or more R_(L); or C₃-C₁₂carbocycle or 3- to 12-membered        heterocycle, each of which is independently optionally        substituted at each occurrence with one or more R_(A);    -   E is independently selected at each occurrence from        C₃-C₁₂carbocycle or 3- to 12-membered heterocycle, and is        independently optionally substituted at each occurrence with one        or more R_(A);    -   R_(D) is each independently selected at each occurrence from        hydrogen or R_(A);    -   R_(A) is independently selected at each occurrence from halogen,        nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, or        -L_(S)-R_(E), wherein two adjacent R_(A), taken together with        the atoms to which they are attached and any atoms between the        atoms to which they are attached, can optionally form carbocycle        or heterocycle;    -   R_(B) and R_(B)′ are each independently selected at each        occurrence from hydrogen; or C₁-C₆alkyl, C₂-C₆alkenyl or        C₂-C₆alkynyl, each of which is independently optionally        substituted at each occurrence with one or more substituents        selected from halogen, hydroxy, mercapto, amino, carboxy, nitro,        oxo, phosphonoxy, phosphono, thioxo, formyl, cyano or 3- to        6-membered carbocycle or heterocycle; or 3- to 6-membered        carbocycle or heterocycle; wherein each 3- to 6-membered        carbocycle or heterocycle in R_(B) or R_(B)′ is independently        optionally substituted at each occurrence with one or more        substituents selected from halogen, hydroxy, mercapto, amino,        carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl,        cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl,        C₂-C₆haloalkenyl or C₂-C₆haloalkynyl;    -   R_(C) is independently selected at each occurrence from        hydrogen, halogen, hydroxy, mercapto, amino, carboxy, nitro,        oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or        C₁-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, hydroxy, mercapto,        amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo,        formyl, cyano or 3- to 6-membered carbocycle or heterocycle; or        3- to 6-membered carbocycle or heterocycle; wherein each 3- to        6-membered carbocycle or heterocycle in R_(C) is independently        optionally substituted at each occurrence with one or more        substituents selected from halogen, hydroxy, mercapto, amino,        carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl,        cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl,        C₂-C₆haloalkenyl or C₂-C₆haloalkynyl;    -   R_(E) is independently selected at each occurrence from        —O—R_(S), —S—R_(S), —C(O)R_(S), —OC(O)R_(S), —C(O)OR_(S),        —N(R_(S)R_(S)′), —S(O)R_(S), —SO₂R_(S), —C(O)N(R_(S)R_(S)′),        —N(R_(S))C(O)R_(S)′, —N(R_(S))C(O)N(R_(S)′R_(S)″),        —N(R_(S))SO₂R_(S)′, —SO₂N(R_(S)R_(S)′),        —N(R_(S))SO₂N(R_(S)′R_(S)″), —N(R_(S))S(O)N(R_(S)′R_(S)″),        —OS(O)—R_(S), —OS(O)₂—R_(S), —S(O)₂OR_(S), —S(O)OR_(S),        —OC(O)OR_(S), —N(R_(S))C(O)OR_(S)′, —OC(O)N(R_(S)R_(S)′),        —N(R_(S))S(O)—R_(S)′, —S(O)N(R_(S)R_(S)′), —P(O)(OR_(S))₂, or        —C(O)N(R_(S))C(O)—R_(S)′; or C₁-C₆alkyl, C₂-C₆alkenyl or        C₂-C₆alkynyl, each of which is independently optionally        substituted at each occurrence with one or more substituents        selected from halogen, hydroxy, mercapto, amino, carboxy, nitro,        oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or        C₃-C₆carbocycle or 3- to 6-membered heterocycle, each of which        is independently optionally substituted at each occurrence with        one or more substituents selected from halogen, hydroxy,        mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,        thioxo, formyl, cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,        C₁-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, C(O)OR_(S),        or —N(R_(S)R_(S)′);    -   R_(F) is independently selected at each occurrence from        C₁-C₁₀alkyl, C₂-C₁₀alkenyl or C₂-C₁₀alkynyl, each of which        contains 0, 1, 2, 3, 4 or 5 heteroatoms selected from O, S or N        and is independently optionally substituted with one or more        R_(L); or —(R_(X)—R_(Y))_(Q)—(R_(X)—R_(Y)′), wherein Q is 0, 1,        2, 3 or 4, and each R_(X) is independently O, S or N(R_(B)),        wherein each R_(Y) is independently C₁-C₆alkylene,        C₂-C₆alkenylene or C₂-C₆alkynylene each of which is        independently optionally substituted with one or more        substituents selected from halogen, hydroxy, mercapto, amino,        carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or        cyano, and wherein each R_(Y)′ is independently C₁-C₆alkyl,        C₂-C₆alkenyl or C₂-C₆alkynyl each of which is independently        optionally substituted with one or more substituents selected        from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,        phosphonoxy, phosphono, thioxo, formyl or cyano;    -   R_(L) is independently selected at each occurrence from halogen,        nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, —O—R_(S),        —S—R_(S), —C(O)R_(S), —OC(O)R_(S), —C(O)OR_(S), —N(R_(S)R_(S)′),        —S(O)R_(S), —SO₂R_(S), —C(O)N(R_(S)R_(S)′) or        —N(R_(S))C(O)R_(S)′; or C₃-C₆carbocycle or 3- to 6-membered        heterocycle, each of which is independently optionally        substituted at each occurrence with one or more substituents        selected from halogen, hydroxy, mercapto, amino, carboxy, nitro,        oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C₁-C₆alkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl, C₂-C₆haloalkenyl or        C₂-C₆haloalkynyl; wherein two adjacent R_(L), taken together        with the atoms to which they are attached and any atoms between        the atoms to which they are attached, can optionally form        carbocycle or heterocycle;    -   L_(S), L_(S)′ and L_(S)″ are each independently selected at each        occurrence from bond; or C₁-C₆alkylene, C₂-C₆alkenylene or        C₂-C₆alkynylene, each of which is independently optionally        substituted at each occurrence with one or more R_(L); and    -   R_(S), R_(S)′ and R_(S)″ are each independently selected at each        occurrence from hydrogen; C₁-C₆alkyl, C₂-C₆alkenyl or        C₂-C₆alkynyl, each of which is independently optionally        substituted at each occurrence with one or more substituents        selected from halogen, hydroxy, mercapto, amino, carboxy, nitro,        oxo, phosphonoxy, phosphono, thioxo, formyl, cyano,        —O—C₁-C₆alkyl, —O—C₁-C₆alkylene-O—C₁-C₆alkyl, or 3- to        6-membered carbocycle or heterocycle; or 3- to 6-membered        carbocycle or heterocycle; wherein each 3- to 6-membered        carbocycle or heterocycle in R_(S), R_(S)′ or R_(S)′ is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, hydroxy, mercapto,        amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo,        formyl, cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,        C₁-C₆haloalkyl, C₂-C₆haloalkenyl or C₂-C₆haloalkynyl.

A and B preferably are independently selected from C₅-C₆carbocycle(e.g., phenyl), 5- to 6-membered heterocycle (e.g., pyridinyl orthiazolyl), or 8- to 12-membered bicycles such as

where Z₁ is independently selected at each occurrence from O, S, NH orCH₂, Z₂ is independently selected at each occurrence from N or CH, Z₃ isindependently selected at each occurrence from N or CH, Z₄ isindependently selected at each occurrence from O, S, NH or CH₂, and W₁,W₂, W₃, W₄, W₅ and W₆ are each independently selected at each occurrencefrom CH or N. A and B are each independently optionally substituted withone or more R_(A).

More preferably. A is selected from C₅-C₆carbocycle, 5- to 6-memberedheterocycle,

and is optionally substituted with one or more R_(A); B is selected fromC₅-C₆carbocycle, 5- to 6-membered heterocycle,

and is optionally substituted with one or more R_(A); where Z₁, Z₂, Z₃,Z₄, W₁, W₂, W₃, W₄, W₅, W₆ are as defined above. Preferably, Z₃ is N andZ₄ is NH. For instance, A can be selected from phenyl (e.g.,

pyridinyl (e.g.,

thiazolyl (e.g.,

(e.g.,

or

(e.g.,

and is optionally substituted with one or more R_(A); and B can beselected from phenyl (e.g.,

pyridinyl (e.g.,

thiazolyl (e.g.,

(e.g.,

or

(e.g.,

and is optionally substituted with one or more R_(A). Highlypreferably, both A and B are phenyl (e.g., both A and B are

Also highly preferably, A is

and B is

or A is

and B is

or A is

and B is

or A is

and B is

or A is

and B is

wherein each A and B is independently optionally substituted with one ormore R_(A).

Also preferably, A is

B is

and A and B are substituted with one or more halogen, such as F or Cl.It was surprisingly discovered that when A and/or B werehalo-substituted benzimidazole (e.g., A is

and B is

the compounds of Formula I (as well as compounds of Formula I_(A),I_(B), I_(C), I_(D), A_(E), I_(F) or I_(G) described below, andcompounds of each embodiment described thereunder) unexpectedly showedsignificantly improved pharmacokinetic properties, as compared tocompounds with unsubstituted benzimidazole. The improvements inpharmacokinetics can be observed, for instance, as a greater totalplasma level exposure, measured as the area under the curve (AUC) over a24 hour period following oral dosing in mouse (for examples see infra).It was also surprisingly discovered that these compounds withhalo-substituted benzimidazole unexpectedly displayed improvedinhibitory activity against certain HCV genotype 1a variants (e.g.,variants containing NS5A mutations L31M, Y93H, or Y93N). Accordingly,the present invention contemplates methods of using such compounds totreat HCV genotype 1a variant infection (e.g., L31M, Y93H, or Y93N 1avariant infection). These methods comprise administering such a compoundto a patient having HCV genotype 1a variant (e.g., L31M, Y93H, or Y93N1a variant). The present invention also contemplates the use of suchcompounds for the manufacture of a medicament for the treatment ofgenotype 1a variant infection (e.g., L31M, Y93H, or Y93N 1a variantinfection).

D preferably is selected from C₅-C₆carbocycle, 5- to 6-memberedheterocycle, or 6- to 12-membered bicycles, and is optionallysubstituted with one or more R_(A). D can also be preferably selectedfrom C₁-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl, and is optionallysubstituted with one or more substituents selected from R_(L). Morepreferably, D is C₅-C₆carbocycle (e.g., phenyl), 5- to 6-memberedheterocycle (e.g., pyridinyl, pyrimidinyl, thiazolyl), or 6- to12-membered bicycles (e.g., indanyl,4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, indazolyl,benzo[d][1,3]dioxol-5-yl), and is substituted with one or more R_(M),where R_(M) is halogen, nitro, oxo, phosphonoxy, phosphono, thioxo,cyano, or -L_(S)-R_(E). Also preferably, D is phenyl, and is optionallysubstituted with one or more R_(A). More preferably, D is phenyl, and issubstituted with one or more R_(M), wherein R_(M) is as defined above.Highly preferably, D is

wherein R_(M) is as defined above, and each R_(N) is independentlyselected from R_(D) and preferably is hydrogen. One or more R_(N) canalso preferably be halo such as F.

D is also preferably pyridinyl, pyrimidinyl, or thiazolyl, optionallysubstituted with one or more R_(A). More preferably D is pyridinyl,pyrimidinyl, or thiazolyl, and is substituted with one or more R_(M).Highly preferably, D is

wherein R_(M) is as defined above, and each R_(N) is independentlyselected from R_(D) and preferably is hydrogen. One or more R_(N) canalso preferably be halo such as F. D is also preferably indanyl,4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, or indazolyl,and is optionally substituted with one or more R_(A). More preferably Dis indanyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl,indazolyl, or benzo[d][1,3]dioxol-5-yl, and is substituted with one ormore R_(M). Highly preferably, D is

and is optionally substituted with one or more R_(M).

Preferably, R_(M) is halogen, hydroxy, mercapto, amino, carboxy, nitro,oxo, phosphonoxy, phosphono, thioxo, cyano; or C₁-C₆alkyl, C₂-C₆alkenylor C₂-C₆alkynyl, each of which is independently optionally substitutedat each occurrence with one or more substituents selected from halogen,hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,thioxo, formyl or cyano; or C₃-C₆carbocycle or 3- to 6-memberedheterocycle, each of which is independently optionally substituted ateach occurrence with one or more substituents selected from halogen,hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,thioxo, formyl, cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆haloalkyl, C₂-C₆haloalkenyl or C₂-C₆haloalkynyl. More preferably,R_(M) is halogen, hydroxy, mercapto, amino, carboxy; or C₁-C₆alkyl,C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is independently optionallysubstituted at each occurrence with one or more substituents selectedfrom halogen, hydroxy, mercapto, amino or carboxy. Highly preferably,R_(M) is C₁-C₆alkyl which is optionally substituted with one or moresubstituents selected from halogen, hydroxy, mercapto, amino or carboxy.

Also preferably, R_(M) is halogen, hydroxy, mercapto, amino, carboxy,nitro, oxo, phosphonoxy, phosphono, thioxo, or cyano; or R_(M) is-L_(S)-R_(E), wherein L_(S) is a bond or C₁-C₆alkylene, and R_(E) is—N(R_(S)R_(S)′), —O—R_(S), —C(O)R_(S), —C(O)OR_(S), —C(O)N(R_(S)R_(S)′),—N(R_(S))C(O)R_(S)′. —N(R_(S))C(O)OR_(S)′, —N(R_(S))SO₂R_(S)′,—SO₂R_(S), —SR_(S), or —P(O)(OR_(S))₂, wherein R_(S) and R_(S)′ can be,for example, each independently selected at each occurrence from (1)hydrogen or (2) C₁-C₆alkyl optionally substituted at each occurrencewith one or more halogen, hydroxy, —O—C₁-C₆alkyl or 3- to 6-memberedheterocycle; or R_(M) is C₁-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl, eachof which is independently optionally substituted at each occurrence withone or more substituents selected from halogen, hydroxy, mercapto,amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl orcyano; or R_(M) is C₃-C₆carbocycle or 3- to 6-membered heterocycle, eachof which is independently optionally substituted at each occurrence withone or more substituents selected from halogen, hydroxy, mercapto,amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl,cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl,C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, —C(O)OR_(S), or —N(R_(S)R_(S)′).More preferably, R_(M) is halogen (e.g., fluoro, chloro, bromo, iodo),hydroxy, mercapto, amino, carboxy, or C₁-C₆alkyl (e.g., methyl,isopropyl, tert-butyl), C₂-C₆alkenyl or C₂-C₆alkynyl, each of which isindependently optionally substituted at each occurrence with one or moresubstituents selected from halogen, hydroxy, mercapto, amino, cyano, orcarboxy. For example R_(M) is CF₃, —C(CF₃)₂—OH, —C(CH₃)₂—CN,—C(CH₃)₂—CH₂OH, or —C(CH₃)₂—CH₂NH₂. Also preferably R_(M) is-L_(S)-R_(E) where L_(S) is a bond and R_(E) is —N(R_(S)R_(S)′),—O—R_(S), —N(R_(S))C(O)OR_(S)′, —N(R_(S))SO₂R_(S)′, —SO₂R_(S), or—SR_(S). For example where L_(S) is a bond, R_(E) is —N(C₁-C₆alkyl)₂(e.g., —NMe₂); —N(C₁-C₆alkylene—O—C₁-C₆alkyl)₂ (e.g. —N(CH₂CH₂OMe)₂);—N(C₁-C₆alkyl)(C₁-C₆alkylene—O—C₁-C₆alkyl) (e.g. —N(CH₃)(CH₂CH₂OMe));—O—C₁-C₆alkyl (e.g., —O-Me, —O-Et, —O-isopropyl, —O-tert-butyl,—O-n-hexyl); —O—C₁-C₆haloalkyl (e.g., —OCF₃, —OCH₂CF₃);—O—C₁-C₆alkylene-piperidine (e.g., —O—CH₂CH₂-1-piperidyl);—N(C₁-C₆alkyl)C(O)OC₁-C₆alkyl (e.g., —N(CH₃)C(O)O—CH₂CH(CH₃)₂),—N(C₁-C₆alkyl)SO₂C₁-C₆alkyl (e.g., —N(CH₃)SO₂CH₃); —SO₂C₁-C₆alkyl (e.g.,—SO₂Me); —SO₂C₁-C₆haloalkyl (e.g., —SO₂CF₃); or —S—C₁-C₆haloalkyl (e.g.,SCF₃). Also preferably R_(M) is -L_(S)-R_(E) where L_(S) isC₁-C₆alkylene (e.g., —CH₂—, —C(CH₃)₂—, —C(CH₃)₂—CH₂—) and R_(E) is—O—R_(S), —C(O)OR_(S), —N(R_(S))C(O)OR_(S)′, or —P(O)(OR_(S))₂. Forexample R_(M) is —C₁-C₆alkylene—O—R_(S) (e.g., —C(CH₃)₂—CH₂—OMe);—C₁-C₆alkylene—C(O)OR_(S) (e.g., —C(CH₃)₂—C(O)OMe);—C₁-C₆alkylene—N(R_(S))C(O)OR_(S)′ (e.g., —C(CH₃)₂—CH₂—NHC(O)OCH₃); or—C₁-C₆alkylene-P(O)(OR_(S))₂ (e.g., —CH₂—P(O)(OEt)₂). Also morepreferably R_(M) is C₃-C₆carbocycle or 3- to 6-membered heterocycle,each of which is independently optionally substituted at each occurrencewith one or more substituents selected from halogen, hydroxy, mercapto,amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl,cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl,C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, —C(O)OR_(S), or —N(R_(S)R_(S)′). Forexample R_(M) is cycloalkyl (e.g., cyclopropyl,2,2-dichloro-1-methylcycloprop-1-yl, cyclohexyl), phenyl, heterocyclyl(e.g., morpholin-4-yl, 1,1-dioxidothiomorpholin-4-yl,4-methylpiperazin-1-yl, 4-methoxycarbonylpiperazin-1-yl,pyrrolidin-1-yl, piperidin-1-yl, 4-methylpiperidin-1-yl,3,5-dimethylpiperidin-1-yl, 4,4-difluoropiperidin-1-yl,tetrahydropyran-4-yl, pyridinyl, pyridin-3-yl,6-(dimethylamino)pyridin-3-yl). Highly preferably, R_(M) is C₁-C₆alkylwhich is optionally substituted with one or more substituents selectedfrom halogen, hydroxy, mercapto, amino or carboxy (e.g., tert-butyl,CF₃).

More preferably, D is C₅-C₆carbocycle, 5- to 6-membered heterocycle or6- to 12-membered bicycle and is substituted with J and optionallysubstituted with one or more R_(A), wherein J is C₃-C₆carbocycle, 3- to6-membered heterocycle or 6- to 12-membered bicycle and is optionallysubstituted with one or more R_(A). Preferably, J is substituted with aC₃-C₆carbocycle or 3- to 6-membered heterocycle, wherein saidC₃-C₆carbocycle or 3- to 6-membered heterocycle is independentlyoptionally substituted with one or more substituents selected fromhalogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy,phosphono, thioxo, formyl, cyano, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₁-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl,C(O)OR_(S) or —N(R_(S)R_(S)′), and J can also be optionally substitutedwith one or more R_(A). Also preferably, D is C₅-C₆carbocycle or 5- to6-membered heterocycle and is substituted with J and optionallysubstituted with one or more R_(A), and J is C₃-C₆carbocycle or 3- to6-membered heterocycle and is optionally substituted with one or moreR_(A), and preferably, J is at least substituted with a C₃-C₆carbocycleor 3- to 6-membered heterocycle which is independently optionallysubstituted with one or more substituents selected from halogen,hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,thioxo, formyl, cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, C(O)OR_(S) or—N(R_(S)R_(S)′). Also preferably, D is C₅-C₆carbocycle or 5- to6-membered heterocycle and is substituted with J and optionallysubstituted with one or more R_(A), and J is 6- to 12-membered bicycle(e.g., a 7- to 12-membered fused, bridged or spiro bicycle comprising anitrogen ring atom through which J is covalently attached to D) and isoptionally substituted with one, or more R_(A). More preferably, D isphenyl and is substituted with J and optionally substituted with one ormore R_(A), and J is C₃-C₆carbocycle, 3- to 6-membered heterocycle or 6-to 12-membered bicycle and is optionally substituted with one or moreR_(A), and preferably J is at least substituted with a C₃-C₆carbocycleor 3- to 6-membered heterocycle which is independently optionallysubstituted with one or more substituents selected from halogen,hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,thioxo, formyl, cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, C(O)OR_(S) or—N(R_(S)R_(S)′). Highly preferably, D is

wherein each R_(N) is independently selected from R_(D) and preferablyis hydrogen or halogen, and J is C₃-C₆carbocycle, 3- to 6-memberedheterocycle or 6- to 12-membered bicycle and is optionally substitutedwith one or more R_(A), and preferably J is at least substituted with aC₃-C₆carbocycle or 3- to 6-membered heterocycle which is independentlyoptionally substituted with one or more substituents selected fromhalogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy,phosphono, thioxo, formyl, cyano, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₁-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl,C(O)OR_(S) or —N(R_(S)R_(S)′). Also preferably, D is

wherein each R_(N) is independently selected from R_(D) and preferablyis hydrogen or halogen, and J is C₃-C₆carbocycle or 3- to 6-memberedheterocycle and is substituted with a C₃-C₆carbocycle or 3- to6-membered heterocycle which is independently optionally substitutedwith one or more substituents selected from halogen, hydroxy, mercapto,amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl,cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl,C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, C(O)OR_(S) or —N(R_(S)R_(S)′), and Jcan also be optionally substituted with one or more R_(A). Alsopreferably, D is

and J is C₃-C₆carbocycle or 3- to 6-membered heterocycle and isoptionally substituted with one or more R_(A), and preferably J is atleast substituted with a C₃-C₆carbocycle or 3- to 6-membered heterocyclewhich is independently optionally substituted with one or moresubstituents selected from halogen, hydroxy, mercapto, amino, carboxy,nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl, C₂-C₆haloalkenyl,C₂-C₆haloalkynyl, C(O)OR_(S) or —N(R_(S)R_(S)′).

It was surprisingly discovered that when D contains a halo-substitutedcarbocycle or heterocycle (e.g., a halo-substituted 5-6 memberedcarbocycle or heterocycle directly linked to X), the compound of FormulaI (as well as compounds of Formula I_(A), I_(B), I_(C), I_(n), I_(E),I_(F) or I_(G) described below, and compounds of each embodimentdescribed thereunder) can exhibit significantly improved inhibitoryactivity against HCV genotypes 2a, 2b, 3a or 4a and/or improvedpharmacokinetic properties. Therefore, the present inventioncontemplates methods of using such compounds to treat HCV genotype 2a,2b, 3a or 4a infection. These methods comprise administering such acompound to a patient having HCV genotype 2a, 2b, 3a or 4a. The presentinvention also contemplates the use of such compounds for themanufacture of a medicament for the treatment of HCV genotypes 2a, 2b,3a or 4a. Suitable D for this purpose can be, for instance,

as described above, wherein at least one R_(N) is halo such as fluorine.Specific examples of suitable D include, but are not limited to,

wherein R_(N), R_(M) and J are as described above.

X preferably is C₅-C₆carbocycle, 5- to 6-membered heterocycle, or 6- to12-membered bicycles, and is optionally substituted with one or moreR_(A) or R_(F). X can also be C₅-C₆carbocycle or 5- to 6-memberedheterocycle which is optionally substituted with one or more R_(A) orR_(F), wherein two adjacent R_(A) on X, taken together with the ringatoms to which they are attached, optionally form a 5- to 6-memberedcarbocycle or heterocycle. Also preferably, X is

wherein X₃ is C(H) or preferably N and is directly appended to -L₃-D; X₄is C₂-C₄alkylene, C₂-C₄alkenylene or C₂-C₄alkynylene, each of whichoptionally contains one or two heteroatoms selected from O, S or N; andX is optionally substituted with one or more R_(A) or R_(F), and twoadjacent R_(A) on X, taken together with the ring atoms to which theyare attached, can optionally form a 5- to 6-membered carbocycle orheterocycle. In addition, X can be

wherein X₃ is C and is directly linked to -L₃-D, X₄ is C₂-C₄alkylene,C₂-C₄alkenylene or C₂-C₄alkynylene each of which optionally contains oneor two heteroatoms selected from O, S or N, and X is optionallysubstituted with one or more R_(A) or R_(E), and two adjacent R_(A) onX, taken together with the ring atoms to which they are attached,optionally form a 5- to 6-membered carbocycle or heterocycle. Moreover,X can be

wherein N is directly linked to L₃-D, X₄ is C₂-C₄alkylene,C₂-C₄alkenylene or C₂-C₄alkynylene each of which optionally contains oneor two heteroatoms selected from O, S or N, and X is optionallysubstituted with one or more R_(A) or R_(F), and two adjacent R_(A) onX, taken together with the ring atoms to which they are attached,optionally form a 5- to 6-membered carbocycle or heterocycle.

For instance, X can be

wherein X₁ is independently selected at each occurrence from CH₂, O, Sor NH, X₂ is independently selected at each occurrence from CH or N, X₃is N and is directly linked to -L₃-D, and X₃′ is C and is directlylinked to -L₃-D; and X is optionally substituted with one or more R_(A)or R_(E), and two adjacent R_(A) on X, taken together with the ringatoms to which they are attached, optionally form a 5- to 6-memberedcarbocycle or heterocycle. For another example, X is

wherein X₁ is independently selected at each occurrence from CH₂, O, Sor NH, X₂ is independently selected at each occurrence from CH or N, X₃is N and is directly linked to -L₃-D, and X₃′ is C and is directlylinked to -L₃-D; and wherein X is optionally substituted with one ormore R_(A) or R_(E), and two adjacent R_(A) on X, taken together withthe ring atoms to which they are attached, optionally form a 5- to6-membered carbocycle or heterocycle.

Highly preferably, X is

wherein X₃ is C(H) or N and is directly linked to -L₃-D, X₃′ is C and isdirectly linked to -L₃-D, and wherein X is optionally substituted withone or more R_(A) or R_(F), and two adjacent R_(A) on X, taken togetherwith the ring atoms to which they are attached, optionally form a 5- to6-membered carbocycle or heterocycle. More preferably, X₃ is N.

Non-limiting examples of X include:

wherein “→” indicates the covalent attachment to -L₃-D. Each X can beoptionally substituted with one or more R_(A) or R_(F), and two adjacentR_(A) on X, taken together with the ring atoms to which they areattached, optionally form a 5- to 6-membered carbocycle or heterocycle.

Non-limiting examples of preferred X include the following pyrrolidinerings, each of which is optionally substituted with one or more R_(A) orR_(F):

As shown, the relative stereochemistry at the 2- and 5-positions of theabove pyrrolidine ring may be either cis or trans. The stereochemistriesof optional substituents R_(A) at the 3- or 4-positions of thepyrrolidine may vary relative to any substituent at any other positionon the pyrrolidine ring. Depending on the particular substituentsattached to the pyrrolidine, the stereochemistry at any carbon may beeither (R) or (S).

Non-limiting examples of preferred X also include the following pyrrole,triazole or thiomorpholine rings, each of which is optionallysubstituted with one or more R_(A) or R_(F):

As shown, the relative stereochemistry at the 3- and 5-positions of thethiomorpholine ring may be either cis or trans. Depending on theparticular substituents attached to the thiomorpholine, thestereochemistry at any carbon may be either (R) or (S).

Also preferably, X is

wherein X₃ is N and is directly linked to -L₃-D, and X is optionallysubstituted with one or more R_(A) or R_(F). Preferably, R_(F) isC₁-C₁₀alkyl, C₂-C₁₀alkenyl or C₂-C₁₀alkynyl, each of which contains 0,1, 2, 3, 4 or 5 heteroatoms selected from O, S or N and is independentlyoptionally substituted with one or more substituents selected fromhalogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy,phosphono, thioxo, formyl or cyano. Also preferably, R_(F) isC₁-C₁₀alkyl, C₂-C₁₀alkenyl or C₂-C₁₀alkynyl, each of which contains 0,1, 2, 3, 4 or 5 O and is independently optionally substituted with oneor more R_(L). Also preferably, R_(F) is—(R_(X)—R_(Y)′)_(Q)—(R_(X)—R_(Y)′), wherein Q is 0, 1, 2, 3 or 4; eachR_(X) is independently O, S or N(R_(B)); each R_(Y) is independentlyC₁-C₆alkylene, C₂-C₆alkenylene or C₂-C₆alkynylene each of which isindependently optionally substituted with one or more substituentsselected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,phosphonoxy, phosphono, thioxo, formyl or cyano; and each R_(Y)′ isindependently C₁-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl each of which isindependently optionally substituted with one or more substituentsselected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,phosphonoxy, phosphono, thioxo, formyl or cyano. Preferably, each R_(X)is O. More preferably, X is optionally substituted with one or moreR_(A) or R_(F), each R_(F) is independently selected from C₁-C₁₀alkyl,C₂-C₁₀alkenyl or C₂-C₁₀alkynyl, each of which contains 0, 1, 2 or 3 Oand is independently optionally substituted with one or moresubstituents selected from halogen, hydroxy, mercapto, amino, carboxy,nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano. Alsopreferably, X is optionally substituted with one or more R_(A) or R_(F),each R_(F) is independently selected from—(O—C₁-C₆alkylene)_(Q)-(O—C₁-C₆alkyl), wherein Q preferably is 0, 1, 2or 3.

L₁ and L₂ are preferably independently bond or C₁-C₆alkylene, L₃ ispreferably selected from bond, C₁-C₆alkylene or —C(O)—, and L₁, L₂, andL₃ are each independently optionally substituted with one or more R_(L).More preferably, L₁, L₂ and L₃ are each independently bond orC₁-C₆alkylene (e.g., —CH₂— or —CH₂CH₂—), and are each independentlyoptionally substituted with one or more R_(L). Highly preferably, L₁, L₂and L₃ are bond.

Y is preferably selected from -L_(S)-C(R₁R₂)N(R₅)-T—R_(D),-L_(S)-C(R₃R₄)C(R₆R₇)-T—R_(D), -G—C(R₁R₂)N(R₅)-T—R_(D),-G—C(R₃R₄)C(R₆R₇)-T—R_(D), —N(R_(B))C(O)C(R₁R₂)N(R₅)-T—R_(D).—N(R_(B))C(O)C(R₃R₄)C(R₆R₇)-T—R_(D),—C(O)N(R_(B))C(R₁R₂)N(R₅)-T—R_(D)—C(O)N(R_(B))C(R₃R₄)C(R₆R₇)-T-R_(D),—N(R_(B))C(O)-L_(S)-E, or —C(O)N(R_(B))-L_(S)-E. G is C₅-C₆carbocycle or5- to 6-membered heterocycle, such as

and is optionally substituted with one or more R_(A) (e.g., one or morechloro or bromo). E preferably is a 7- to 12-membered bicycle (such as

wherein U is independently selected at each occurrence from —(CH₂)— or—(NH)—; V and Z₂₀ are each independently selected from C₁-C₄alkylene,C₂-C₄alkenylene or C₂-C₄alkynylene, in which at least one carbon atomcan be independently optionally replaced with O, S or N), and isindependently optionally substituted with one or more R_(A). Morepreferably, R₁ is R_(C), and R₂ and R₅, taken together with the atoms towhich they are attached, form a 5- to 6-membered heterocycle or 6- to12-membered bicycle (e.g.,

which is optionally substituted with one or more R_(A) (such as, but notlimited to hydroxy, halo (e.g., fluoro), C₁-C₆alkyl (e.g., methyl), orC₂-C₆alkenyl (e.g., allyl)); and R₃ and R₆ are each independently R_(C),and R₄ and R₇, taken together with the atoms to which they are attached,form a 5- to 6-membered carbocycle/heterocycle or 6- to 12-memberedbicycle (e.g.,

which is optionally substituted with one or more R_(A) (such as, but notlimited to hydroxy, halo (e.g., fluoro), C₁-C₆alkyl (e.g., methyl), orC₂-C₆alkenyl (e.g., allyl)).

Y can also be selected from -M—C(R₁R₂)N(R₅)—C(O)-L_(Y)′-M′—R_(D),-M—C(R₁R₂)N(R₅)-L_(Y)′-M′—R_(D),-L_(S)-C(R₁R₂)N(R₅)—C(O)-L_(Y)′-M′—R_(D),-L_(S)-C(R₁R₂)N(R₅)-L_(Y)′-M′—R_(D),-M—C(R₃R₄)C(R₆R₇)—C(O)-L_(Y)′-M′—R_(D),-M—C(R₃R₄)C(R₅R₇)-L_(Y)′-M′—R_(D),-L_(S)-C(R₃R₄)C(R₆R₇)—C(O)-L_(Y)′-M′—R_(D), or-L_(S)-C(R₃R₄)C(R₆R₇)-L_(Y)′-M′—R_(D), wherein M preferably is bond,—C(O)N(R_(B))— or —N(R_(B))C(O)—, M′ preferably is bond, —C(O)N(R_(B))—:—N(R_(B))C(O)—, —N(R_(B))C(O)O—, N(R_(B))C(O)N(R_(B)′)-, —N(R_(B))S(O)—or —N(R_(B))S(O)₂—, and L_(Y)′ preferably is C₁-C₆alkylene which isoptionally substituted with one or more R_(L). L_(Y)′, for example, is aC₁-C₆alkylene such as, but not limited to,

and the optional R_(L) is a substituent such as, but not limited tophenyl, —SMe, or methoxy. Any stereochemistry at a carbon within thegroup L_(Y)′ can be either (R) or (S). More preferably, R₁ is R_(C), andR₂ and R₅, taken together with the atoms to which they are attached,form a 5- to 6-membered heterocycle or 6- to 12-membered bicycle (e.g.,

which is optionally substituted with one or more R_(A) (e.g., one ormore hydroxy); and R₃ and R₆ are each independently R_(C), and R₄ andR₇, taken together with the atoms to which they are attached, form a 5-to 6-membered carbocycle/heterocycle or 6- to 12-membered bicycle (e.g.,

which is optionally substituted with one or more R_(A).

Also preferably, Y is selected from—N(R_(B))CO—C(R₁R₂)N(R₅)—C(O)-L_(Y)′—N(R_(B))C(O)O—R_(D),—N(R_(B))CO—C(R₁R₂)N(R₅)—C(O)-L_(Y)′—N(R_(B))C(O)—R_(D),—N(R_(B))CO—C(R₁R₂)N(R₅)—C(O)-L_(Y)-N(R_(B))S(O)₂—R_(D),—N(R_(B))CO—C(R₁R₂)N(R₅)—C(O)-L_(Y)′—N(R_(B)R_(B)′)—R_(D),—N(R_(B))CO—C(R₁R₂)N(R₅)—C(O)-L_(Y)′—O—R_(D),—N(R_(B))CO—C(R₁R₂)N(R₅)—C(O)-L_(Y)′—R_(D),—N(R_(B))CO—C(R₁R₂)N(R₅)—R_(D),-L_(S)-C(R₁R₂)N(R₅)—C(O)-L_(Y)′—N(R_(B))C(O)O—R_(D),-L_(S)-C(R₁R₂)N(R₅)—C(O)-L_(Y)′—N(R_(B))C(O)—R_(D),-L_(S)-C(R₁R₂)N(R₅)—C(O)-L_(Y)′—N(R_(B))S(O)₂—R_(D),-L_(S)-C(R₁R₂)N(R₅)—C(O)-L_(Y)′—N(R_(B)R_(B)′)—R_(D),-L_(S)-C(R₁R₂)N(R₅)—C(O)-L_(Y)′—O—R_(D),-L_(S)-C(R₁R₂)N(R₅)—C(O)-L_(Y)′—R_(D), -L_(S)-C(R₁R₂)N(R₅)—R_(D),—N(R_(B))CO—C(R₃R₄)C(R₆R₇)—C(O)-L_(Y)′—N(R_(B))C(O)O—R_(D),—N(R_(B))CO—C(R₃R₄)C(R₆R₇)—C(O)-L_(Y)′—N(R_(B))C(O)—R_(D),—N(R_(B))CO—C(R₃R₄)C(R₆R₇)—C(O)-L_(Y)′—N(R_(B))S(O)₂—R_(D),—N(R_(B))CO—C(R₃R₄)C(R₆R₇)—C(O)-L_(Y)′—N(R_(B)R_(B))—R_(D),—N(R_(B))CO—C(R₃R₄)C(R₆R₇)—C(O)-L_(Y)′—O—R_(D),—N(R_(B))CO—C(R₃R₄)C(R₆R₇)—C(O)-L_(Y)′—R_(D),—N(R_(B))CO—C(R₃R₄)C(R₆R₇)R_(D),-L_(S)-C(R₃R₄)C(R₆R₇)—C(O)-L_(Y′)—N(R_(B))C(O)O—R_(D),-L_(S)-C(R₃R₄)C(R₆R₇)—C(O)-L_(Y)′—N(R_(B))C(O)—R_(D),-L_(S)-C(R₃R₄)C(R₆R₇)—C(O)-L_(Y)′—N(R_(B))S(O)₂—R_(D),-L_(S)-C(R₃R₄)C(R₆R₇)—C(O)-L_(Y)′—N(R_(B)R_(B)′)—R_(D),-L_(S)—C(R₃R₄)C(R₆R₇)—C(O)-L_(Y)′—O—R_(D),-L_(S)-C(R₃R₄)C(R₆R₇)—C(O)-L_(Y)′—R_(D), or -L_(S)-C(R₃R₄)C(R₆R₇)—R_(D),wherein L_(Y)′ preferably is C₁-C₆alkylene which is optionallysubstituted with one or more R_(L). R₁ may be R_(C), and R₂ and R₅,taken together with the atoms to which they are attached, may form a 5-to 6-membered heterocycle or 6- to 12-membered bicycle (e.g.,

which is optionally substituted with one or more R_(A); and R₃ and R₆may be each independently R_(C), and R₄ and R₇, taken together with theatoms to which they are attached, may form a 5- to 6-memberedcarbocycle/heterocycle or 6- to 12-membered bicycle (e.g.,

which is optionally substituted with one or more R_(A).

Highly preferably, Y is selected from—N(R_(E)″)CO—C(R₁R₂)N(R₅)—C(O)-L_(Y)-N(R_(E)″)C(O)-L_(S)-R_(E) or—C(R₁R₂)N(R₅)—C(O)-L_(Y)-N(R_(B)″)C(O)-L_(S)-R_(E), or Y is-G—C(R₁R₂)N(R₅)—C(O)-L_(Y)-N(R_(B)″)C(O)-L_(S)-R_(E), wherein L_(Y) isC₁-C₆alkylene optionally substituted with one or more R_(L), and R_(B)″is each independently R_(B). R_(B)″ and R₁ are each preferably hydrogenor C₁-C₆alkyl, and R₂ and R₅, taken together with the atoms to whichthey are attached, preferably form a 5- to 6-membered heterocycle or 6-to 12-membered bicycle (e.g.,

which is optionally substituted with one or more R_(A) (such as, but notlimited to hydroxy, halo (e.g., fluoro), C₁-C₆alkyl (e.g., methyl), orC₂-C₆alkenyl (e.g., allyl)). Preferably, L_(Y) is C₁-C₆alkylenesubstituted with one or more R_(L) such as a C₃-C₆carbocycle or 3- to6-membered heterocycle which is independently optionally substitutedwith one or more substituents selected from halogen, hydroxy, mercapto,amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl,cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl,C₂-C₆haloalkenyl or C₂-C₆haloalkynyl. Highly preferably, L_(Y) is aC₁-C₆alkylene such as, but not limited to,

(stereochemistry at a carbon within the group L_(Y) can be either (R) or(S)), L_(Y) is independently optionally substituted with one or moreR_(L) (e.g., one or more phenyl or methoxy), G preferably is

R_(B)″ is hydrogen; —C(R₁R₂)N(R_(S))— is

L_(S) is a bond; and R_(E) is methoxy.

Non-limiting examples of preferred Y include:

wherein T and R_(D) are as defined herein. T, for example, can be-L_(S)-M-L_(S)′-M′-L_(S)″— where L_(S) is a bond; M is C(O); L_(S)′ isC₁-C₆alkylene such as, but not limited to,

where L_(S)′ is independently optionally substituted with one or moreR_(L); R_(L) is a substituent such as, but not limited to phenyl ormethoxy; M′ is —NHC(O)— or —NMeC(O)—; and L_(S)″ is a bond. Anystereochemistry at a carbon within the group L_(S)′ can be either (R) or(S). R_(D), for example is methoxy. T-R_(D) includes, but is not limitedto:

T-R_(D) may also include certain stereochemical configurations; thusT-R_(D) includes, but is not limited to:

Non-limiting examples of preferred Y also include:

Z is preferably selected from -L_(S)-C(R₈R₉)N(R₁₂)-T—R_(D),-L_(S)-C(R₁₀R₁₁)C(R₁₃R₁₄)-T—R_(D), -G-C(R₈R₉)N(R₁₂)-T—R_(D),-G—C(R₁₀R₁₁)C(R₁₃R₁₄)-T—R_(D), —N(R_(B))C(O)C(R₈R₉)N(R₁₂)-T—R_(D),—N(R_(B))C(O)C(R₁₀R₁₁)C(R₁₃R₁₄)-T—R_(D),—C(O)N(R_(B))C(R₈R₉)N(R₁₂)-T—R_(D),—C(O)N(R_(B))C(R₁₀R₁₁)C(R₁₃R₁₄)-T—R_(D), —N(R_(B))C(O)-L_(S)-E, or—C(O)N(R_(B))-L_(S)-E. G is C₅-C₆carbocycle or 5- to 6-memberedheterocycle, such as

and is optionally substituted with one or more R_(A) (e.g., one or morechloro or bromo).E preferably is a 8- to 12-membered bicycle (such as

wherein U is independently selected at each occurrence from —(CH₂)— or—(NH)—; and V and Z₂₀ are each independently selected fromC₁-C₄alkylene, C₂-C₄alkenylene or C₂-C₄alkynylene, in which at least onecarbon atom is independently optionally replaced with O, S or N), and isindependently optionally substituted with one or more R_(A). Morepreferably, R₈ is R_(C), and R₉ and R₁₂, taken together with the atomsto which they are attached, form a 5- to 6-membered heterocycle or 6- to12-membered bicycle (e.g.,

which is optionally substituted with one or more R_(A) (such as, but notlimited to hydroxy, halo (e.g., fluoro), C₁-C₆alkyl (e.g., methyl), orC₂-C₆alkenyl (e.g., allyl)); and R₁₀ and R₁₃ are each independentlyR_(C), and R₁₁ and R₁₄, taken together with the atoms to which they areattached, form a 5- to 6-membered carbocycle/heterocycle or 6- to12-membered bicycle (e.g.,

which is optionally substituted with one or more R_(A) (such as, but notlimited to hydroxy, halo (e.g., fluoro), C₁-C₆alkyl (e.g., methyl), orC₂-C₆alkenyl (e.g., allyl)).

Z can also be selected from -M—C(R₈R₉)N(R₁₂)—C(O)-L_(Y)′-M′—R_(D),-M—C(R₈t₉)N(R₁₂)-L_(Y)′-M′—R_(D),-L_(S)-C(R₈R₉)N(R₁₂)—C(O)-L_(Y)′-M′—R_(D),-L_(S)-C(R₈R₉)N(R₁₂)-L_(Y)′-M′—R_(D),-M—C(R₁₀R₁₁)C(R₁₃R₁₄)—C(O)-L_(Y)′-M—C(R₁₀R₁₁)C(R₁₃R₁₄)-L_(Y)′-M′—R_(D),-L_(S)—C(R₁₀R₁₁)C(R₁₃R₁₄)—C(O)-L_(Y)-M′—R_(D), or-L_(S)-C(R₁₀R₁₁)C(R₁₃R₁₄)-L_(Y)′-M′—R_(D), wherein M preferably is bond,—C(O)N(R_(B))— or —N(R_(B))C(O)—, M′ preferably is bond, —C(O)N(R_(B))—,—N(R_(B))C(O)—, —N(R_(B))C(O)O—, N(R_(B))C(O)N(R_(B)′)-, —N(R_(B))S(O)—or —N(R_(B))S(O)₂—, and L_(Y)′ preferably is C₁-C₆alkylene which isindependently optionally substituted with one or more R_(L). L_(Y)′, forexample, is a C₁-C₆alkylene such as, but not limited to,

and the optional R_(L) is a substituent such as, but not limited tophenyl, —SMe, or methoxy. Any stereochemistry at a carbon within thegroup L_(Y)′ can be either (R) or (S). More preferably, R₈ is R_(C), andR₉ and R₁₂, taken together with the atoms to which they are attached,form a 5- to 6-membered heterocycle or 6- to 12-membered bicycle (e.g.,

which is optionally substituted with one or more R_(A) (e.g., one ormore hydroxy); and R₁₀ and R₁₃ are each independently R_(C), and R₁₁ andR₁₄, taken together with the atoms to which they are attached form a 5-to 6-membered carbocycle/heterocycle or 6- to 12-membered bicycle (e.g.,

which is optionally substituted with one or more R_(A).

Also preferably, Z is selected from—N(R_(B))CO—C(R₈R₉)N(R₁₂)—C(O)-L_(Y)′—N(R_(B))C(O)O—R_(D),—N(R_(B))CO—C(R₈R₉)N(R₁₂)—C(O)-L_(Y)′—N(R_(B))C(O)—R_(D),—N(R_(B))CO—C(R₈R₉)N(R₁₂)—C(O)-L_(Y)′—N(R_(B))S(O)₂—R_(D),—N(R_(B))CO—C(R₈R₉)N(R₁₂)—C(O)-L_(Y)′—N(R_(B)R_(B)′)—R_(D),—N(R_(B))CO—C(R₈R₉)N(R₁₂)—C(O)-L_(Y)′—O—R_(D),—N(R_(B))CO—C(R₈R₉)N(R₁₂)—C(O)-L_(Y)′—R_(D),—N(R_(B))CO—C(R₈R₉)N(R₁₂)—R_(D),-L_(S)-C(R₈R₉)N(R₁₂)—C(O)-L_(Y)′—N(R_(B))C(O)O—R_(D),-L_(S)-C(R₈R₉)N(R₁₂)—C(O)-L_(Y)′—N(R_(B))C(O)—R_(D),-L_(S)-C(R₈R₉)N(R₁₂)—C(O)-L_(Y)′—N(R_(B))S(O)₂—R_(D),-L_(S)-C(R₈R₉)N(R₁₂)—C(O)-L_(Y)′—N(R_(B)R_(B)′)—R_(D),-L_(S)-C(R₈R₉)N(R₁₂)—C(O)-L_(Y)′—O—R_(D),-L_(S)-C(R₈R₉)N(R₁₂)—C(O)-L_(Y)′—R_(D), -L_(S)-C(R₈R₉)N(R₁₂)—R_(D),—N(R_(B))CO—C(R₁₀R₁₁)C(R₁₃R₁₄)—C(O)-L_(Y)′—N(R_(B))C(O)O—R_(D),—N(R_(B))CO—C(R₁₀R₁₁)C(R₁₃R₁₄)—C(O)-L_(Y)′—N(R_(B))C(O)—R_(D),—N(R_(B))CO—C(R₁₀R₁₁)C(R₁₃R₁₄)—C(O)-L_(Y)′—N(R_(B))S(O)₂—R_(D),—N(R_(B))CO—C(R₁₀R₁₁)C(R₁₃R₁₄)—C(O)-L_(Y)′—N(R_(B)R_(B)′)—R_(D),—N(R_(B))CO—C(R₁₀R₁₁)C(R₁₃R₁₄)—C(O)-L_(Y)′—O—R_(D),—N(R_(B))CO—C(R₁₀R₁₁)C(R₁₃R₁₄)—C(O)-L_(Y)′R_(D),—N(R_(B))CO—C(R₁₀R₁₁)C(R₁₃R₁₄)—R_(D),-L_(S)-C(R₁₀R₁₁)C(R₁₃R₁₄)—C(O)-L_(Y)′—N(R_(B))C(O)O—R_(D),-L_(S)-C(R₁₀R₁₁)C(R₁₃R₁₄)—C(O)-L_(Y)′—N(R_(B))C(O)—R_(D),-L_(S)-C(R₁₀R₁₁)C(R₁₃R₁₄)—C(O)-L_(Y)′—N(R_(B))S(O)₂—R_(D),-L_(S)-C(R₁₀R₁₁)C(R₁₃R₁₄)—C(O)-L_(Y)′—N(R_(B)R_(B)′)—R_(D),-L_(S)-C(R₁₀R₁₁)C(R₁₃R₁₄)—C(O)-L_(Y)′—O—R_(D),-L_(S)-C(R₁₀R₁₁)C(R₁₃R₁₄)—C(O)-L_(Y)′—R_(D), or-L_(S)-C(R₁₀R₁₁)C(R₁₃R₁₄)—R_(D), wherein L_(Y)′ preferably isC₁-C₆alkylene which is independently optionally substituted with one ormore R_(L). R₈ may be R_(C), and R₉ and R₁₂, taken together with theatoms to which they are attached, may form a 5- to 6-memberedheterocycle or 6- to 12-membered bicycle (e.g.,

which is optionally substituted with one or more R_(A); and R₁₀ and R₁₃may be each independently R_(C), and R₁₁ and R₁₄, taken together withthe atoms to which they are attached, may form a 5- to 6-memberedcarbocycle/heterocycle or 6- to 12-membered bicycle (e.g.,

which is optionally substituted with one or more R_(A).

Highly preferably, Z is selected from—N(R_(B)″)CO—C(R₈R₉)N(R₁₂)—C(O)-L_(Y)-N(R₁₃″)C(O)-L_(S)-R_(E) or—C(R₈R₉)N(R₁₂)—C(O)-L_(Y)-N(R_(B)″)C(O)-L_(S)-R_(E), or Z is-G—C(R₈R₉)N(R₁₂)—C(O)-L_(Y)-N(R_(B)″)C(O)-L_(S)-R_(E), wherein L_(Y) isC₁-C₆alkylene optionally substituted with one or more R_(L), and R_(B)″is each independently R_(B). R_(B)″ and R₈ are each preferably hydrogenor C₁-C₆alkyl, and R₉ and R₁₂, taken together with the atoms to whichthey are attached, preferably form a 5- to 6-membered heterocycle or 6-to 12-membered bicycle (e.g.,

which is optionally substituted with one or more R_(A) (such as, but notlimited to hydroxy, halo (e.g., fluoro), C₁-C₆alkyl (e.g., methyl), orC₂-C₆alkenyl (e.g., allyl)). Preferably, L_(Y) is C₁-C₆alkylenesubstituted with one or more R_(L) such as a C₃-C₆carbocycle or 3- to6-membered heterocycle which is independently optionally substitutedwith one or more substituents selected from halogen, hydroxy, mercapto,amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl,cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl,C₂-C₆haloalkenyl or C₂-C₆haloalkynyl. Highly preferably, L_(Y) is aC₁-C₆alkylene such as, but not limited to,

(stereochemistry at a carbon within the group L_(Y) can be either (R) or(S)); L_(Y) is independently optionally substituted with one or moreR_(L) (e.g., one or more phenyl or methoxy); G preferably is

R_(B)″ is hydrogen; —C(R₈R₉)N(R₁₂)— is

L_(S) is a bond; and R_(E) is methoxy.

Non-limiting examples of preferred Z include:

wherein T and R_(D) are as defined herein. T, for example, can be-L_(S)-M-L_(S)′-M′-L_(S)″- where L_(S) is a bond; M is C(O); L_(S)′ isC₁-C₆alkylene such as, but not limited to,

where L_(S)′ is independently optionally substituted with one or moreR_(L); the optional R_(L) is a substituent such as, but not limited tophenyl or methoxy; M′ is —NHC(O)— or —NMeC(O)—; and L_(S)″ is a bond.Any stereochemistry at a carbon within the group L_(S)′ can be either(R) or (S). R_(D), for example is methoxy. T-R_(D) includes, but is notlimited to:

T-R_(D) may also include certain stereochemical configurations; thusT-R_(D) includes, but is not limited to:

Non-limiting examples of preferred Z also include:

T can be, without limitation, independently selected at each occurrencefrom —C(O)-L_(S)′-, —C(O)O-L_(S)′-, —C(O)-L_(S)′-N(R_(B))C(O)-L_(S)″—,—C(O)-L_(S)′-N(R_(B))C(O)O-L_(S)″—,—N(R_(B))C(O)-L_(S)′-N(R_(B))C(O)-L_(S)″—,—N(R_(B))C(O)-L_(S)′-N(R_(B))C(O)O-L_(S)″—, or—N(R_(B))C(O)-L_(S)′-N(R_(B))-L_(S)″—. Preferably, T is independentlyselected at each occurrence from —C(O)-L_(S)′-M′-L_(S)″- or—N(R_(B))C(O)-L_(S)′-M′-L_(S)″—. More preferably, T is independentlyselected at each occurrence from —C(O)-L_(S)′-N(R_(B))C(O)-L_(S)″- or—C(O)-L_(S)′-N(R_(B))C(O)O-L_(S)″—.

T can also be, for example, -L_(S)-M-L_(S)′-M′-L_(S)″- where L_(S) is abond; M is C(O); L_(S)′ is C₁-C₆alkylene (e.g.,

where L_(S)′ is independently optionally substituted with R_(T); theoptional R_(T) is a substituent selected from —C₁-C₆alkyl,—C₂-C₆alkenyl, —C₁-C₆alkyl-OH, —C₁-C₆alkyl-O—C₁-C₆alkyl, 3- to6-membered heterocycle (e.g., tetrahydrofuranyl), or C₃-C₆carbocyclyl(e.g., phenyl, cyclohexyl); M′ is —NHC(O)—, —N(Et)C(O)— or —N(Me)C(O)—;and L_(S)″ is a bond. R_(D) preferably is hydrogen, —C₁-C₆alkyl (e.g.,methyl), —O—C₁-C₆alkyl (e.g., methoxy, tert-butoxy), methoxymethyl, or—N(C₁-C₆alkyl)₂ (e.g., —NMe₂).

T-R_(D) can be, without limitation,

wherein the stereochemistry at a carbon within the group T-R_(D) can beeither (R) or (S).

T can also be, without limitation, -L_(S)-M-L_(S)′- where L_(S) is abond; M is C(O); L_(S)′ is C₁-C₆alkylene (e.g.,

where L_(S)′ is independently optionally substituted with R_(T); theoptional R_(T) is a substituent selected from —C₁-C₆alkyl,—C₁-C₆alkyl-OH, —C₁-C₆alkyl-O—C₁-C₆alkyl, or a C₃-C₆carbocyclyl (e.g.,phenyl, cyclohexyl). R_(D), for example is —OH; —OC(O)Me;—NH(C₁-C₆alkyl) (e.g., —NHMe, —NHEt); —N(C₁-C₆alkyl)₂ (e.g., —NMe₂,—NEt₂); a 3- to 10-membered heterocyclyl (e.g., pyrrolidinyl,imidazolidinyl, hexahydropyrimidinyl, morpholinyl, piperidinyl)optionally substituted with one or more halogen, oxo; C₃-C₁₀carbocycle(e.g., cyclopentyl) optionally substituted with —OH; —C₁-C₆alkyl (e.g.,isopropyl, 3-pentyl) optionally substituted with —OH; or NHR_(T) whereR_(T) is a 3- to 6-membered heterocyclyl (e.g., thiazolyl, pyrimidinyl).T-R_(D) includes, but is not limited to:

wherein the stereochemistry at a carbon within the group T-R_(D) can beeither (R) or (S).

For each compound of Formula I, L_(K) can also be independently selectedat each occurrence from a bond; -L_(S)′-N(R_(B))C(O)-L_(S)-;-L_(S)′-C(O)N(R_(B))-L_(S)-; or C₁-C₆alkylene, C₂-C₆alkenylene,C₂-C₆alkynylene, C₃-C₁₀carbocycle or 3- to 10-membered heterocycle, eachof which is independently optionally substituted at each occurrence withone or more substituents selected from halogen, R_(T.)—O—R_(S),—S—R_(S), —N(R_(S)R_(S)′), —OC(O)R_(S), —C(O)OR_(S), nitro, oxo,phosphonoxy, phosphono, thioxo, formyl or cyano, wherein R_(T), R_(B),R_(S), R_(S)′, L_(S) and L_(S)′ are as defined above.

For Formula I as well as Formulae I_(A), I_(D), I_(C), I_(D), I_(E),I_(F) or I_(D) described below, including each and every embodimentdescribed thereunder, R_(A) preferably is halogen, hydroxy, mercapto,amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; orC₁-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is independentlyoptionally substituted at each occurrence with one or more substituentsselected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,phosphonoxy, phosphono, thioxo, formyl or cyano; or C₃-C₆carbocycle or3- to 6-membered heterocycle, each of which is independently optionallysubstituted at each occurrence with one or more substituents selectedfrom halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,phosphonoxy, phosphono, thioxo, formyl, cyano, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₁-C₆haloalkyl, C₂-C₆haloalkenyl or C₂-C₆haloalkynyl; or-L_(A)-O—R_(S), -L_(A)-S—R_(S), -L_(A)-C(O)R_(S), -L_(A)-OC(O)R_(S),-L_(A)-C(O)OR_(S), -L_(A)-N(R_(S)R_(S)′), -L_(A)-S(O)R_(S),-L_(A)-SO₂R_(S), -L_(A)-C(O)N(R_(S)R_(S)′), -L_(A)-N(R_(S))C(O)R_(S)′,-L_(A)-N(R_(S))C(O)N(R_(S)′R_(S)″), -L_(A)-N(R_(S))SO₂R_(S)′,-L_(A)-SO₂N(R_(S)R_(S)′), -L_(A)-N(R_(S))SO₂N(R_(S)′R_(S)″),-L_(A)-N(R_(S))S(O)N(R_(S)′R_(S)″), -L_(A)-OS(O)—R_(S),-L_(A)-OS(O)₂—R_(S), -L_(A)-S(O)₂OR_(S), -L_(A)-S(O)OR_(S),-L_(A)-OC(O)OR_(S), -L_(A)-N(R_(S))C(O)OR_(S)′,-L_(A)-OC(O)N(R_(S)R_(S)′), -L_(A)-N(R_(S))S(O)—R_(S)′,-L_(A)-S(O)N(R_(S)R_(S)′) or -L_(A)-C(O)N(R_(S))C(O)—R_(S)′, whereinL_(A) is bond, C₁-C₆alkylene, C₂-C₆alkenylene or C₂-C₆alkynylene.

More preferably, R_(A) is halogen, hydroxy, mercapto, amino, carboxy,nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or C₁-C₆alkyl,C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is independently optionallysubstituted at each occurrence with one or more substituents selectedfrom halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,phosphonoxy, phosphono, thioxo, formyl or cyano; or C₃-C₆carbocycle or3- to 6-membered heterocycle, each of which is independently optionallysubstituted at each occurrence with one or more substituents selectedfrom halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,phosphonoxy, phosphono, thioxo, formyl, cyano, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₁-C₆haloalkyl, C₂-C₆haloalkenyl or C₂-C₆haloalkynyl.

Highly preferably, R_(A) is halogen, hydroxy, mercapto, amino, carboxy,nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or C₁-C₆alkyl,C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is independently optionallysubstituted at each occurrence with one or more substituents selectedfrom halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,phosphonoxy, phosphono, thioxo, formyl or cyano.

L_(S), L_(S)′ and L_(S)″ preferably are each independently selected ateach occurrence from bond; or C₁-C₆alkylene, C₂-C₆alkenylene orC₂-C₆alkynylene.

A and B can be the same or different. Likewise, L₁ and L₂, or Y and Z,or Y-A- and Z—B—, or -A-L₁- and —B-L₂-, can be the same or different. Insome instances, Y-A-L₁- is identical to Z—B-L₂-. In some otherinstances, Y-A-L₁- is different from Z—B-L₂-.

In one embodiment, A and B are each independently 5- or 6-memberedcarbocycle or heterocycle (e.g., phenyl such as

and are each independently optionally substituted with one or moreR_(A). X is 5- or 6-membered carbocycle or heterocycle or 6- to12-membered bicycle (e.g.,

wherein X₃ is N and is directly linked to -L₃-D) and is optionallysubstituted with one or more R_(A). Specific examples of X are describedhereinabove. D is C₅-C₆carbocycle or 5- to 6-membered heterocycle (e.g.,phenyl), and is optionally substituted with one or more R_(A), or issubstituted with J and optionally substituted with one or more R_(A),wherein J is C₃-C₆carbocycle, 3- to 6-membered heterocycle or 6- to12-membered bicycle and is optionally substituted with one or moreR_(A). Preferably, J is substituted with a C₃-C₆carbocycle or 3- to6-membered heterocycle which is independently optionally substitutedwith one or more substituents selected from halogen, hydroxy, mercapto,amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl,cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl,C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, C(O)OR_(S) or —N(R_(S)R_(S)′), and Jcan also be optionally substituted with one or more R_(A). Preferably, Dis

wherein R_(M) and R_(N) are as defined above. Also preferably, D is

wherein J and R_(N) are as defined above. L₁ and L₂ are eachindependently bond or C₁-C₆alkylene, and L₃ is bond, C₁-C₆alkylene or—C(O)—, and L₁, L₂, and L₃ are each independently optionally substitutedwith one or more R_(L). Preferably, L₁, L₂, and L₃ are bond. Y is—N(R_(B))C(O)C(R₁R₂)N(R₅)-T—R_(D), or—N(R_(B))C(O)C(R₃R₄)C(R₆R₇)-T—R_(D), and Z is—N(R_(B))C(O)C(R₈R₉)N(R₁₂)-T—R_(D), or—N(R_(B))C(O)C(R₁₀R₁₁)C(R₁₃R₁₄)-T—R_(D). R₁ is R_(C), and R₂ and R₅,taken together with the atoms to which they are attached, form a 5- to6-membered heterocyclic ring (e.g.,

which is optionally substituted with one or more R_(A); R₃ and R₆ areeach independently R_(C), and R₄ and R₇, taken together with the atomsto which they are attached, form a 5- to 6-membered carbocyclic orheterocyclic ring (e.g.,

which is optionally substituted with one or more R_(A). R₈ is R_(C), andR₉ and R₁₂, taken together with the atoms to which they are attached,form a 5- to 6-membered heterocyclic ring (e.g.,

which is optionally substituted with one or more R_(A); and R₁₀ and R₁₃are each independently R_(C), and R₁₁ and R₁₄, taken together with theatoms to which they are attached, form a 5- to 6-membered carbocyclic orheterocyclic ring (e.g.,

which is optionally substituted with one or more R_(A). T is preferablyindependently selected at each occurrence from—C(O)-L_(Y)′—N(R_(B))C(O)-L_(S)″— or —C(O)-L_(Y)′—N(R_(B))C(O)O-L_(S)″—.L_(Y)′ is each independently L_(S)′ and, preferably, is eachindependently C₁-C₆alkylene (e.g., —CH₂— or

and optionally substituted with one or more substituents selected fromR_(L). T can also be, without limitation, selected from—C(O)-L_(Y)′-L_(S)″—, —C(O)-L_(Y)′—O-L_(S)″—,—C(O)-L_(Y)′—N(R_(B))-L_(S)″—, or —C(O)-L_(Y)′—N(R_(B))S(O)₂-L_(S)″—. Insome cases, at least one of Y and Z is, or both Y and Z areindependently,

wherein non-limiting examples of R_(D) include (1) —O—C₁-C₆alkyl,—O—C₂-C₆alkenyl, —O—C₂-C₆alkynyl, C₁-C₆alkyl, C₂-C₆alkenyl orC₂-C₆alkynyl, each of which is independently optionally substituted ateach occurrence with one or more substituents selected from halogen,hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,thioxo, formyl, cyano, C₃-C₆carbocycle or 3- to 6-membered heterocycle;or (2) C₃-C₆carbocycle or 3- to 6-membered heterocycle each of which isindependently optionally substituted at each occurrence with one or moresubstituents selected from halogen, hydroxy, mercapto, amino, carboxy,nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl, C₂-C₆haloalkenyl orC₂-C₆haloalkynyl; and non-limiting examples of L_(Y)′ includeC₁-C₆alkylene optionally substituted with halogen, hydroxy, mercapto,amino, carboxy, phosphonoxy, —O—C₁-C₆alkyl, —O—C₂-C₆alkenyl,—O—C₂-C₆alkynyl, or 3- to 6-membered carbocycle or heterocycle, said 3-to 6-membered carbocycle or heterocycle being optionally substitutedwith one or more substituents selected from halogen, hydroxy, mercapto,amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl,cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl,C₂-C₆haloalkenyl or C₂-C₆haloalkynyl.

In another embodiment, A is

and is optionally substituted with one or more R_(A); B is

and is optionally substituted with one or more R_(A). Z₁ isindependently selected at each occurrence from O, S, NH or CH₂; and Z₂is independently selected at each occurrence from N or CH. Preferably, Ais

B is

and A and B are substituted with one or more halogen, such as F or Cl.When A and/or B are halo-substituted benzimidazole (e.g., A is

and B is

the compounds of this embodiment can have significantly improvedpharmacokinetic properties as well as improved inhibitory activityagainst certain HCV genotype 1a mutants, as compared to the samecompounds but with unsubstituted benzimidazole. X is 5- or 6-memberedcarbocycle or heterocycle or 6- to 12-membered bicycle (e.g.,

wherein X₃ is N and is directly linked to -L₃-D) and is optionallysubstituted with one or more R_(A). Specific examples of X are describedhereinabove. D is C₅-C₆carbocycle or 5- to 6-membered heterocycle (e.g.,phenyl), and is optionally substituted with one or more R_(A), or issubstituted with J and optionally substituted with one or more R_(A),wherein J is C₃-C₆carbocycle, 3- to 6-membered heterocycle or 6- to12-membered bicycle and is optionally substituted with one or moreR_(A). Preferably, J is substituted with a C₃-C₆carbocycle or 3- to6-membered heterocycle which is independently optionally substitutedwith one or more substituents selected from halogen, hydroxy, mercapto,amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl,cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl,C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, C(O)OR_(S) or —N(R_(S)R_(S)′), and Jcan also be optionally substituted with one or more R_(A). Preferably, Dis

wherein R_(M) and R_(N) are as defined above. Also preferably, D is

wherein J and R_(N) are as defined above. L₁ and L₂ are eachindependently bond or C₁-C₆alkylene, and L₃ is bond, C₁-C₆alkylene or—C(O)—, and L₁, L₂, and L₃ are each independently optionally substitutedwith one or more R_(L). Preferably, L₁, L₂, and L₃ are bond. Y is-L_(S)-C(R₁R₂)N(R₅)-T—R_(D) or -L_(S)-C(R₃R₄)C(R₆R₂)-T—R_(D), and Z is-L_(S)-C(R₈R₉)N(R₁₂)-T—R_(D) or -L_(S)-C(R₁₀R₁₁)C(R₁₃R₁₄)-T—R_(D). R₁ isR_(C), and R₂ and R₅, taken together with the atoms to which they areattached, form a 5- to 6-membered heterocyclic ring (e.g.,

which is optionally substituted with one or more R_(A); R₃ and R₆ areeach independently R_(C), and R₄ and R₇, taken together with the atomsto which they are attached, form a 5- to 6-membered carbocyclic orheterocyclic ring (e.g.,

which is optionally substituted with one or more R_(A). R₈ is R_(C), andR₉ and R₁₂, taken together with the atoms to which they are attached,form a 5- to 6-membered heterocyclic ring (e.g.,

which is optionally substituted with one or more R_(A); and R₁₀ and R₁₃are each independently R_(C), and R₁₁ and R₁₄, taken together with theatoms to which they are attached, form a 5- to 6-membered carbocyclic orheterocyclic ring (e.g.,

which is optionally substituted with one or more R_(A). T is preferablyindependently selected at each occurrence from—C(O)-L_(Y)′—N(R_(B))C(O)-L_(S)″— or —C(O)-L_(Y)′—N(R_(B))C(O)O-L_(S)″—.L_(Y)′ is each independently L_(S)′ and, preferably, is independentlyC₁-C₆alkylene (e.g., —CH₂—) and optionally substituted with one or moresubstituents selected from R_(L). T can also be, without limitation,selected from —C(O)-L_(Y)′-L_(S)″—, —C(O)-L_(Y)′—O-L_(S)″—,—C(O)-L_(Y)′—N(R_(B))-L_(S)″—, or —C(O)-L_(Y)′—N(R_(B))S(O)₂-L_(S)″—. Insome cases, at least one of Y and Z is, or both Y and Z areindependently,

wherein non-limiting examples of R_(D) include (1) —O—C₁-C₆alkyl,—O—C₂-C₆alkenyl, —O—C₂-C₆alkynyl, C₁-C₆alkyl, C₂-C₆alkenyl orC₂-C₆alkynyl, each of which is independently optionally substituted ateach occurrence with one or more substituents selected from halogen,hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,thioxo, formyl, cyano, C₃-C₆carbocycle or 3- to 6-membered heterocycle;or (2) C₃-C₆carbocycle or 3- to 6-membered heterocycle each of which isindependently optionally substituted at each occurrence with one or moresubstituents selected from halogen, hydroxy, mercapto, amino, carboxy,nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl, C₂-C₆haloalkenyl orC₂-C₆haloalkynyl; and non-limiting examples of L_(Y)′ includeC₁-C₆alkylene optionally substituted with halogen, hydroxy, mercapto,amino, carboxy, phosphonoxy, —O—C₁-C₆alkyl, —O—C₂-C₆alkenyl,—O—C₂-C₆alkynyl, or 3- to 6-membered carbocycle or heterocycle, said 3-to 6-membered carbocycle or heterocycle being optionally substitutedwith one or more substituents selected from halogen, hydroxy, mercapto,amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl,cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl,C₂-C₆haloalkenyl or C₂-C₆haloalkynyl.

In still yet another embodiment, A and B are each independently 5- or6-membered carbocycle or heterocycle (e.g., A and B are eachindependently phenyl, such as

and are each independently optionally substituted with one or moreR_(A). X is 5- or 6-membered carbocycle or heterocycle or 6- to12-membered bicycle (e.g.,

wherein X₃ is N and is directly linked to -L₃-D) and is optionallysubstituted with one or more R_(A). Specific examples of X are describedhereinabove. D can be, for example, C₅-C₆carbocycle or 5- to 6-memberedheterocycle (e.g., phenyl), and is optionally substituted with one ormore R_(A), or is substituted with J and optionally substituted with oneor more R_(A), wherein J is C₃-C₆carbocycle, 3- to 6-memberedheterocycle or 6- to 12-membered bicycle and is optionally substitutedwith one or more R_(A). Preferably, J is substituted with aC₃-C₆carbocycle or 3- to 6-membered heterocycle which is independentlyoptionally substituted with one or more substituents selected fromhalogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy,phosphono, thioxo, formyl, cyano, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₁-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl,C(O)OR_(S) or —N(R_(S)R_(S)′), and J can also be optionally substitutedwith one or more R_(A). Preferably, D is

wherein R_(M) and R_(N) are as defined above. Also preferably, D is

wherein J and R_(N) are as defined above. L₁ and L₂ are eachindependently bond or C₁-C₆alkylene, and L₃ is bond, C₁-C₆alkylene or—C(O)—, and L₁, L₂, and L₃ are each independently optionally substitutedwith one or more R_(L). Preferably, L₁, L₂, and L₃ are bond. Y is-G-C(R₁R₂)N(R₅)-T—R_(D) or -G—C(R₃R₄)C(R₆R₇)-T—R_(D), and Z is-G—C(R₈R₉)N(R₁₂)-T—R_(D) or -G—C(R₁₀R₁₁)C(R₁₃R₁₄)-T—R_(D). G isindependently C₅-C₆carbocycle or 5- to 6-membered heterocycle, such as

and is independently optionally substituted with one or more R_(A). R₁is R_(C), and R₂ and R₅, taken together with the atoms to which they areattached, form a 5- to 6-membered heterocyclic ring (e.g.,

which is optionally substituted with one or more R_(A); R₃ and R₆ areeach independently R_(C), and R₄ and R₂, taken together with the atomsto which they are attached, form a 5- to 6-membered carbocyclic orheterocyclic ring (e.g.,

which is optionally substituted with one or more R_(A). R₈ is R_(C), andR₉ and R₁₂, taken together with the atoms to which they are attached,form a 5- to 6-membered heterocyclic ring (e.g.,

which is optionally substituted with one or more R_(A); and R₁₀ and R₁₃are each independently R_(C), and R₁₁ and R₁₄, taken together with theatoms to which they are attached, form a 5- to 6-membered carbocyclic orheterocyclic ring (e.g.,

which is optionally substituted with one or more R_(A). T is preferablyindependently selected at each occurrence from—C(O)-L_(Y)′—N(R_(B))C(O)-L_(S)″— or —C(O)-L_(Y)′—N(R_(B))C(O)O-L_(S)″—.L_(Y)′ is each independently L_(S)′ and, preferably, is eachindependently C₁-C₆alkylene (e.g., —CH₂— or

and optionally substituted with one or more substituents selected fromR_(L). T can also be, without limitation, selected from—C(O)-L_(Y)′-L_(S)″—, —C(O)-L_(Y)′—O-L_(S)″—,—C(O)-L_(Y)′—N(R_(B))-L_(S)″—, or —C(O)-L_(Y)′—N(R_(B))S(O)₂-L_(S)″—. Insome cases, at least one of Y and Z is, or both Y and Z areindependently,

wherein non-limiting examples of R_(D) include (1) —O—C₁-C₆alkyl,—O—C₂-C₆alkenyl, —O—C₂-C₆alkynyl, C₁-C₆alkyl, C₂-C₆alkenyl orC₂-C₆alkynyl, each of which is independently optionally substituted ateach occurrence with one or more substituents selected from halogen,hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,thioxo, formyl, cyano, C₃-C₆carbocycle or 3- to 6-membered heterocycle;or (2) C₃-C₆carbocycle or 3- to 6-membered heterocycle each of which isindependently optionally substituted at each occurrence with one or moresubstituents selected from halogen, hydroxy, mercapto, amino, carboxy,nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl, C₂-C₆haloalkenyl orC₂-C₆haloalkynyl; and non-limiting examples of L_(Y)′ includeC₁-C₆alkylene optionally substituted with halogen, hydroxy, mercapto,amino, carboxy, phosphonoxy, —O—C₁-C₆alkyl, —O—C₂-C₆alkenyl,—O—C₂-C₆alkynyl, or 3- to 6-membered carbocycle or heterocycle, said 3-to 6-membered carbocycle or heterocycle being optionally substitutedwith one or more substituents selected from halogen, hydroxy, mercapto,amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl,cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl,C₂-C₆haloalkenyl or C₂-C₆haloalkynyl.

In yet another embodiment, A and B are each independently 5- or6-membered carbocycle or heterocycle (e.g., A and B are eachindependently phenyl, such as

and are each independently optionally substituted with one or moreR_(A). X is 5- or 6-membered carbocycle or heterocycle or 6- to12-membered bicycle (e.g.,

wherein X₃ is N and is directly linked to -L₃-D) and is optionallysubstituted with one or more R_(A). Specific examples of X are describedhereinabove. D can be, for example, C₅-C₆carbocycle or 5- to 6-memberedheterocycle (e.g., phenyl), and is optionally substituted with one ormore R_(A), or is substituted with J and optionally substituted with oneor more R_(A), wherein J is C₃-C₆carbocycle, 3- to 6-memberedheterocycle or 6- to 12-membered bicycle and is optionally substitutedwith one or more R_(A). Preferably, J is substituted with aC₃-C₆carbocycle or 3- to 6-membered heterocycle which is independentlyoptionally substituted with one or more substituents selected fromhalogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy,phosphono, thioxo, formyl, cyano, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₁-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl,C(O)OR_(S) or —N(R_(S)R_(S)′), and J can also be optionally substitutedwith one or more R_(A). Preferably, D is

wherein R_(M) and R_(N) are as defined above. Also preferably, D is

wherein J and R_(N) are as defined above. L₁ and L₂ are eachindependently bond or C₁-C₆alkylene, and L₃ is bond, C₁-C₆alkylene or—C(O)—, and L₁, L₂, and L₃ are each independently optionally substitutedwith one or more R_(L). Preferably, L₁, L₂, and L₃ are bond. Y is—N(R_(B))C(O)C(R₁R₂)N(R₃)-T-R_(D) or—N(R_(B))C(O)C(R₃R₄)C(R₆R₇)-T-R_(D), and Z is -G—C(R₈R₉)N(R₁₂)-T-R_(D)or -G—C(R₁₀R₁₁)C(R₁₃R₁₄)-T-R_(D); or Y is -G—C(R₁R₂)N(R₅)-T-R_(D) or-G—C(R₃R₄)C(R₆R₇)-T-R_(D), and Z is —N(R_(B))C(O)C(R₈R₉)N(R₁₂)-T-R_(D)or —N(R_(B))C(O)C(R₁₀R₁₁)C(R₁₃R₁₄)-T-R_(D). R₁ is R_(C), and R₂ and R₅,taken together with the atoms to which they are attached, form a 5- to6-membered heterocyclic ring (e.g.,

which is optionally substituted with one or more R_(A); R₃ and R₆ areeach independently R_(C), and R₄ and R₇, taken together with the atomsto which they are attached, form a 5- to 6-membered carbocyclic orheterocyclic ring (e.g.,

which is optionally substituted with one or more R_(A). R₈ is R_(C), andR₉ and R₁₂, taken together with the atoms to which they are attached,form a 5- to 6-membered heterocyclic ring (e.g.,

which is optionally substituted with one or more R_(A); and R₁₀ and R₁₃are each independently R_(C), and R₁₁ and R₁₄, taken together with theatoms to which they are attached, form a 5- to 6-membered carbocyclic orheterocyclic ring (e.g.,

which is optionally substituted with one or more R_(A). G isindependently C₅-C₆carbocycle or 5- to 6-membered heterocycle, such as

and is independently optionally substituted with one or more R_(A). T ispreferably independently selected at each occurrence from—C(O)-L_(Y)′—N(R₈)C(O)-L_(S)″— or —C(O)-L_(Y)′—N(R₈)C(O)O-L_(S)″—.L_(Y)′ is each independently L_(S)′ and, preferably, is eachindependently C₁-C₆alkylene (e.g., —CH₂— or

and optionally substituted with one or more substituents selected fromR_(L). T can also be, without limitation, selected from—C(O)-L_(Y)′-L_(S)″—, —C(O)-L_(Y)′—O-L_(S)″—, or—C(O)-L_(Y)′—N(R_(B))S(O)₂-L_(S)″—. In some cases, Y is

as described above, and Z is

as described above. In some other cases, Y is

as described above, and Z is

as described above.

In still another embodiment, A is 5- or 6-membered carbocycle orheterocycle (e.g., phenyl such as

and B is

or A is

(e.g.,

or B is 5- or 6-membered carbocycle or heterocycle (e.g., phenyl such as

A and B are each independently optionally substituted with one or moreR_(A). Z₁ is independently selected at each occurrence from O, S, NH orCH₂; and Z₂ is independently selected at each occurrence from N or CH. Xis 5- or 6-membered carbocycle or heterocycle or 6- to 12-memberedbicycle (e.g.,

wherein X₃ is N and is directly linked to -L₃-D) and is optionallysubstituted with one or more R_(A). Specific examples of X are describedhereinabove. D is C₅-C₆carbocycle or 5- to 6-membered heterocycle (e.g.,phenyl), and is optionally substituted with one or more R_(A), or issubstituted with J and optionally substituted with one or more R_(A),wherein J is C₃-C₆carbocycle, 3- to 6-membered heterocycle or 6- to12-membered bicycle and is optionally substituted with one or moreR_(A). Preferably, J is substituted with a C₃-C₆carbocycle or 3- to6-membered heterocycle which is independently optionally substitutedwith one or more substituents selected from halogen, hydroxy, mercapto,amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl,cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl,C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, C(O)OR_(S) or —N(R_(S)R_(S)′), and Jcan also be optionally substituted with one or more R_(A). Preferably, Dis

wherein R_(M), and R_(N) are as defined above. Also preferably, D is

wherein J and R_(N) are as defined above. L₁ and L₂ are eachindependently bond or C₁-C₆alkylene, and L₃ is bond, C₁-C₆alkylene or—C(O)—, and L₁, L₂, and L₃ are each independently optionally substitutedwith one or more R_(L). Preferably, L₁, L₂, and L₃ are bond. When A is5- or 6-membered carbocycle or heterocycle (e.g., phenyl such as

Y is —N(R_(B))C(O)C(R₁R₂)N(R₅)-T—R_(D),—N(R_(B))C(O)C(R₃R₄)C(R₆R₇)-T—R_(D), -G—C(R₁R₂)N(R₅)-T—R_(D) or-G-C(R₃R₄)C(R₆R₇)-T—R_(D), and Z is -L_(S)-C(R₈R₉)N(R₁₂)-T—R_(D) or-L_(S)-C(R₁₀R₁₁)C(R₁₃R₁₄)-T—R_(D). When B is 5- or 6-membered carbocycleor heterocycle (e.g., phenyl such as

Y is -L_(S)-C(R₁R₂)N(R₅)-T—R_(D) or -L_(S)-C(R₃R₄)C(R₆R₇)-T—R_(D), and Zis —N(R_(B))C(O)C(R₈R₉)N(R₁₂)-T—R_(D),—N(R_(B))C(O)C(R₁₀R₁₁)C(R₁₃R₁₄)-T—R_(D), -G—C(R₈R₉)N(R₁₂)—I—R_(D) or-G—C(R₁₀R₁₁)C(R₁₃R₁₄)-T—R_(D). R₁ is R_(C), and R₂ and R₅, takentogether with the atoms to which they are attached, form a 5- to6-membered heterocyclic ring (e.g.,

which is optionally substituted with one or more R_(A); R₃ and R₆ areeach independently R_(C), and R₄ and R₇, taken together with the atomsto which they are attached, form a 5- to 6-membered carbocyclic orheterocyclic ring (e.g.,

which is optionally substituted with one or more R_(A). R₈ is R_(C), andR₉ and R₁₂, taken together with the atoms to which they are attached,form a 5- to 6-membered heterocyclic ring (e.g.,

which is optionally substituted with one or more R_(A); and R₁₀ and R₁₃are each independently R_(C), and R₁₁ and R₁₄, taken together with theatoms to which they are attached, form a 5- to 6-membered carbocyclic orheterocyclic ring (e.g.,

which is optionally substituted with one or more R_(A). G isindependently C₅-C₆carbocycle or 5- to 6-membered heterocycle, such as

and is independently optionally substituted with one or more R_(A). T ispreferably independently selected at each occurrence from—C(O)-L_(Y)′—N(R_(B))C(O)-L_(S)″- or —C(O)-L_(Y)′—N(R_(B))C(O)O-L_(S)″—.L_(Y)′ is each independently L_(S)′ and, preferably, is eachindependently C₁-C₆alkylene (e.g., —CH₂— or

and optionally substituted with one or more substituents selected fromR_(L). T can also be, without limitation, selected from—C(O)-L_(Y)′-L_(S)″—, —C(O)-L_(Y)′—O-L_(S)″—, or—C(O)-L_(Y)′—N(R_(B))S(O)₂-L_(S)″—. In some cases when A is 5- or6-membered carbocycle or heterocycle (e.g., phenyl such as

Y is

as described above, and Z is

as described above. In some other cases when B is 5- or 6-memberedcarbocycle or heterocycle (e.g., phenyl such as

Y is

as described above, and Z is

as described above.

The present invention also features compounds of Formulae I, I_(A),I_(B), I_(C) and I_(D) as described herein (including each embodimentdescribed hereunder) and pharmaceutically acceptable salts thereof,wherein:

-   -   D is C₃-C₁₂carbocycle or 3- to 12-membered heterocycle, and is        optionally substituted with one or more R_(A); or D is        C₃-C₁₂carbocycle or 3- to 12-membered heterocycle which is        substituted with J and optionally substituted with one or more        R_(A), where J is C₃-C₁₅carbocycle or 3- to 15-membered        heterocycle (e.g., a 3- to 6-membered monocycle, a 6- to        12-membered fused, bridged or spiro bicycle, a 10- to        15-membered tricycle containing fused, bridged or spiro rings,        or a 13- to 15-membered carbocycle or heterocycle) and is        optionally substituted with one or more R_(A), or J is —SF₅; or        D is hydrogen or R_(A);    -   R_(A) is independently selected at each occurrence from halogen,        nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, or        -L_(B)-R_(E); wherein two adjacent R_(A), taken together with        the atoms to which they are attached and any atoms between the        atoms to which they are attached, can optionally form carbocycle        or heterocycle;    -   L_(B) is independently selected at each occurrence from L_(S);        or C₁-C₁₀alkylene, C₂-C₁₀alkenylene or C₂-C₁₀alkynylene, each of        which optionally has 1, 2, 3, 4 or 5 carbon atoms independently        replaced with O, S or N(R_(B)), and each of said C₁-C₁₀alkylene,        C₂-C₁₀alkenylene or C₂-C₁₀alkynylene being independently        optionally substituted with one or more R_(L);    -   R_(E) is independently selected at each occurrence from        —O—R_(S), —S—R_(S), —C(O)R_(S), —OC(O)R_(S), —C(O)OR_(S),        —N(R_(S)R_(S)′), —S(O)R_(S), —SO₂R_(S), —C(O)N(R_(S)R_(S)′),        —N(R_(S))C(O)R_(S)′, —N(R_(S))C(O)N(R_(S)′R_(S)″),        —N(R_(S))SO₂R_(S)′, —SO₂N(R_(S)R_(S)′),        —N(R_(S))SO₂N(R_(S)′R_(S)″), —N(R_(S))S(O)N(R_(S)′R_(S)″),        —OS(O)—R_(S), —OS(O)₂—R_(S), —S(O)₂OR_(S), —S(O)OR_(S),        —OC(O)OR_(S), —N(R_(S))C(O)OR_(S)′, —OC(O)N(R_(S)R_(S)′),        —N(R_(S))S(O)—R_(S)′, —S(O)N(R_(S)R_(S)′), —P(O)(OR_(S))₂,        ═C(R_(S)R_(S)′), or —C(O)N(R_(S))C(O)—R_(S)′; or C₁-C₆alkyl,        C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is independently        optionally substituted at each occurrence with one or more        substituents selected from halogen, hydroxy, mercapto, amino,        carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl,        cyano, C₃-C₁₂carbocycle or 3- to 12-membered heterocycle; or        C₃-C₁₂carbocycle or 3- to 12-membered heterocycle (e.g., 7- to        12-membered carbocycle or heterocycle), each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, hydroxy, mercapto,        amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo,        formyl, cyano, trimethylsilyl, C₁-C₆alkyl, C₂-C₆alkenyl,        C₂-C₆alkynyl, C₁-C₆haloalkyl, C₂-C₆haloalkenyl,        C₂-C₆haloalkynyl, —O—R_(S), —S—R_(S), —C(O)R_(S), —C(O)OR_(S),        or —N(R_(S)R_(S)′).    -   R_(L) is independently selected at each occurrence from halogen,        nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, —O—R_(S),        —S—R_(S), —C(O)R_(S), —OC(O)R_(S), —C(O)OR_(S), —N(R_(S)R_(S)′),        —S(O)R_(S), —SO₂R_(S), —C(O)N(R_(S)R_(S)′) or        —N(R_(S))C(O)R_(S)′; or C₃-C₁₂carbocycle or 3- to 12-membered        heterocycle (e.g., C₃-C₆carbocycle or 3- to 6-membered        heterocycle), each of which is independently optionally        substituted at each occurrence with one or more substituents        selected from halogen, hydroxy, mercapto, amino, carboxy, nitro,        oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C₁-C₆alkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl, C₂-C₆haloalkenyl or        C₂-C₆haloalkynyl; wherein two adjacent R_(L), taken together        with the atoms to which they are attached and any atoms between        the atoms to which they are attached, can optionally form        carbocycle or heterocycle.

In one embodiment, A and B are each independently 5- or 6-memberedcarbocycle or heterocycle (preferably, A and B are each independentlyphenyl such as

and are each independently optionally substituted with one or more R_(A)(preferably, A and B are each independently substituted with at leastone halo such as F). X is 5- or 6-membered carbocycle or heterocycle or6- to 12-membered bicycle (preferably, X is

wherein X₃ is N and is directly linked to -L₃-D), and is optionallysubstituted with one or more R_(A). D is a C₅-C₆carbocycle or 5- to6-membered heterocycle (e.g., phenyl), and is substituted with J andoptionally substituted with one or more R_(A). J is C₃-C₆carbocycle, 3-to 6-membered heterocycle, 6- to 12-membered bicycle, 10- to 15-memberedtricycle, or 13- to 15-membered carbocycle/heterocycle, and J isoptionally substituted with one or more R_(A). Preferably, J issubstituted with a C₃-C₆carbocycle, 3- to 6-membered heterocycle, 6- to12-membered bicycle or 7- to 12-membered carbocycle/heterocycle, whichis independently optionally substituted with one or more substituentsselected from (1) halogen, hydroxy, mercapto, amino, carboxy, nitro,oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl, C₂-C₆haloalkenyl,C₂-C₆haloalkynyl, —C(O)OR_(S) or —N(R_(S)R_(S)′), or (2) trimethylsilyl,—O—R_(S), —S—R_(S), —C(O)R_(S); and J can also be optionally substitutedwith one or more R_(A). Preferably, D is

wherein J is as defined above, and each R_(N) is independently selectedfrom R_(D) and preferably is hydrogen or halo such as F. L₁ and L₂ areeach independently bond or C₁-C₆alkylene, and L₃ is bond, C₁-C₆alkyleneor —C(O)—, and L₁, L₂, and L₃ are each independently optionallysubstituted with one or more R_(L). Preferably, L₁, L₂, and L₃ are bond.Y is —N(R_(B))C(O)C(R₁R₂)N(R₅)-T—R_(D),—N(R_(B))C(O)C(R₃R₄)C(R₆R₇)-T—R_(D), -G—C(R₁R₂)N(R₅)-T—R_(D) or-G—C(R₃R₄)C(R₆R₇)-T-R_(D). Z is —N(R_(B))C(O)C(R₈R₉)N(R₁₂)-T—R_(D),—N(R_(B))C(O)C(R₁₀R₁₁)C(R₁₃R₁₄)-T—R_(D), -G—C(R₈R₉)N(R₁₂)-T—R_(D) or-G—C(R₁₀R₁₁)C(R₁₃R₁₄)-T—R_(D). R₁ is R_(C); and R₂ and R₅, takentogether with the atoms to which they are attached, form a 5- to6-membered heterocyclic ring (e.g.,

or 6- to 12-membered bicycle (e.g.,

which is optionally substituted with one or more R_(A); R₃ and R₆ areeach independently R_(C), and R₄ and R₇, taken together with the atomsto which they are attached, form a 5- to 6-membered carbocyclic orheterocyclic ring (e.g.,

or 6- to 12-membered bicycle which is optionally substituted with one ormore R_(A). R₈ is R_(C); and R₉ and R₁₂, taken together with the atomsto which they are attached, form a 5- to 6-membered heterocyclic ring(e.g.,

or 6- to 12-membered bicycle (e.g.,

which is optionally substituted with one or more R_(A); and R₁₀ and R₁₃are each independently R_(C), and R₁₁ and R₁₄, taken together with theatoms to which they are attached, form a 5- to 6-membered carbocyclic orheterocyclic ring (e.g.,

or 6- to 12-membered bicycle which is optionally substituted with one ormore R_(A). G is independently C₅-C₆carbocycle or 5- to 6-memberedheterocycle, such as

and is independently optionally substituted with one or more R_(A). T ispreferably independently selected at each occurrence from—C(O)-L_(Y)′—N(R_(B))C(O)-L_(S)″— or —C(O)-L_(Y)′—N(R_(B))C(O)O-L_(S)″—.L_(Y)′ is each independently L_(S)′ and, preferably, is eachindependently C₁-C₆alkylene (e.g., —CH₂— or

and optionally substituted with one or more substituents selected fromR_(L). T can also be, without limitation, selected from—C(O)-L_(Y)′-L_(S)″—, —C(O)-L_(Y)′—O-L_(S)″—,—C(O)-L_(Y)′—N(R_(B))-L_(S)″—, or —C(O)-L_(Y)′—N(R_(B))S(O)₂-L_(S)″—. Insome cases, Y is

as described above, and Z is

as described above.

In another embodiment, A is

and is optionally substituted with one or more R_(A); B is

and is optionally substituted with one or more R_(A). Z₁ isindependently selected at each occurrence from O, S, NH or CH₂; and Z₂is independently selected at each occurrence from N or CH. Preferably, Aand B are each independently substituted with at least one halo such asF. Also preferably, A is

B is

and A and B are substituted with one or more halogen, such as F or Cl.When A and/or B are halo-substituted benzimidazole (e.g., A is

and B is

the compounds of this embodiment can have significantly improvedpharmacokinetic properties as well as improved inhibitory activityagainst certain HCV genotype 1a mutants, as compared to the samecompounds but with unsubstituted benzimidazole. X is 5- or 6-memberedcarbocycle or heterocycle or 6- to 12-membered bicycle (preferably, X is

wherein X₃ is N and is directly linked to -L₃-D), and is optionallysubstituted with one or more R_(A). D is a C₅-C₆carbocycle or 5- to6-membered heterocycle (e.g., phenyl), and is substituted with J andoptionally substituted with one or more R_(A). J is C₃-C₆carbocycle, 3-to 6-membered heterocycle, 6- to 12-membered bicycle, 10- to 15-memberedtricycle or 13- to 15-membered carbocycle/heterocycle, and J isoptionally substituted with one or more R_(A). Preferably, J issubstituted with a C₃-C₆carbocycle, 3- to 6-membered heterocycle, 6- to12-membered bicycle or 7- to 12-membered carbocycle/heterocycle, whichis independently optionally substituted with one or more substituentsselected from (1) halogen, hydroxy, mercapto, amino, carboxy, nitro,oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl, C₂-C₆haloalkenyl,C₂-C₆haloalkynyl, —C(O)OR_(S) or —N(R_(S)R_(S)′), or (2) trimethylsilyl,—O—R_(S), —S—R_(S), or —C(O)R_(S); and J can also be optionallysubstituted with one or more R_(A). Preferably, D is

wherein J is as defined above, and each R_(N) is independently selectedfrom R_(D) and preferably is hydrogen or halo such as F. L₁ and L₂ areeach independently bond or C₁-C₆alkylene, and L₃ is bond, C₁-C₆alkyleneor —C(O)—, and L₁, L₂, and L₃ are each independently optionallysubstituted with one or more R_(L). Preferably, L₁, L₂, and L₃ are bond.Y is -L_(S)-C(R₁R₂)N(R₅)-T—R_(D) or -L_(S)-C(R₃R₄)C(R₆R₂)-T—R_(D). Z is-L_(S)-C(R₈R₉)N(R₁₂)-T—R_(D) or -L_(S)-C(R₁₀R₁₁)C(R₁₃R₁₄)-T—R_(D). R₁ isR_(C); and R₂ and R₅, taken together with the atoms to which they areattached, form a 5- to 6-membered heterocyclic ring (e.g.,

or 6- to 12-membered bicycle (e.g.,

which is optionally substituted with one or more R_(A); R₃ and R₆ areeach independently R_(C), and R₄ and R₇, taken together with the atomsto which they are attached, form a 5- to 6-membered carbocyclic orheterocyclic ring (e.g.,

or 6- to 12-membered bicycle which is optionally substituted with one ormore R_(A). R₈ is R_(C); and R₉ and R₁₂, taken together with the atomsto which they are attached, form a 5- to 6-membered heterocyclic ring(e.g.,

or 6- to 12-membered bicycle (e.g.,

which is optionally substituted with one or more R_(A); and R₁₀ and R₁₃are each independently R_(C), and R₁₁ and R₁₄, taken together with theatoms to which they are attached, form a 5- to 6-membered carbocyclic orheterocyclic ring (e.g.,

or 6- to 12-membered bicycle which is optionally substituted with one ormore R_(A). T is preferably independently selected at each occurrencefrom —C(O)-L_(Y)′—N(R_(B))C(O)-L_(S)″- or—C(O)-L_(Y)′—N(R_(B))C(O)O-L_(S)″—. L_(Y)′ is each independently L_(S)′and, preferably, is each independently C₁-C₆alkylene (e.g., —CH₂— or

and optionally substituted with one or more substituents selected fromR_(L). T can also be, without limitation, selected from—C(O)-L_(Y)′-L_(S)″—, —C(O)-L_(Y)′—O-L_(S)″—,—C(O)-L_(Y)′—N(R_(B))-L_(S)″—, or —C(O)-L_(Y)′—N(R_(B))S(O)₂-L_(S)″—. Insome cases, Y and Z are independently

wherein non-limiting examples of R_(D) include (1) —O—C₁-C₆alkyl,—O—C₂-C₆alkenyl, —O—C₂-C₆alkynyl, C₁-C₆alkyl, C₂-C₆alkenyl orC₂-C₆alkynyl, each of which is independently optionally substituted ateach occurrence with one or more substituents selected from halogen,hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,thioxo, formyl, cyano, C₃-C₆carbocycle or 3- to 6-membered heterocycle;or (2) C₃-C₆carbocycle or 3- to 6-membered heterocycle each of which isindependently optionally substituted at each occurrence with one or moresubstituents selected from halogen, hydroxy, mercapto, amino, carboxy,nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl, C₂-C₆haloalkenyl orC₂-C₆haloalkynyl; and non-limiting examples of L_(Y)′ includeC₁-C₆alkylene optionally substituted with halogen, hydroxy, mercapto,amino, carboxy, phosphonoxy, —O—C₁-C₆alkyl, —O—C₂-C₆alkenyl,—O—C₂-C₆alkynyl, or 3- to 6-membered carbocycle or heterocycle, said 3-to 6-membered carbocycle or heterocycle being optionally substitutedwith one or more substituents selected from halogen, hydroxy, mercapto,amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl,cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl,C₂-C₆haloalkenyl or C₂-C₆haloalkynyl.

In another aspect, the present invention features compounds of FormulaI_(A) and pharmaceutically acceptable salts thereof.

wherein:

-   -   R_(NB) is each independently selected from R_(B);    -   R_(C)′ is each independently selected from R_(C);    -   R_(D)′ is each independently selected from R_(D);    -   R₂ and R₅, taken together with the atoms to which they are        attached, form a 3- to 12-membered heterocycle which is        optionally substituted with one or more R_(A);    -   R₉ and R₁₂, taken together with the atoms to which they are        attached, form a 3- to 12-membered heterocycle which is        optionally substituted with one or more R_(A);    -   A, B, D, X, L₁, L₂, L₃, T, R_(A), R_(B), R_(C), and R_(D) are as        described above in Formula I.

In this aspect, A and B preferably are independently selected fromC₅-C₆carbocycle or 5- to 6-membered heterocycle, and are eachindependently optionally substituted with one or more R_(A). Morepreferably, at least one of A and B is phenyl (e.g.,

and is optionally substituted with one or more R_(A). Highly preferably,both A and B are each independently phenyl (e.g.,

and are each independently optionally substituted with one or moreR_(A).

D preferably is selected from C₅-C₆carbocycle, 5- to 6-memberedheterocycle, or 8- to 12-membered bicycles, and is optionallysubstituted with one or more R_(A). D can also be preferably selectedfrom C₁-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl, and is optionallysubstituted with one or more R_(L). More preferably, D isC₅-C₆carbocycle, 5- to 6-membered heterocycle, or 6- to 12-memberedbicycles, and is substituted with one or more R_(M), where R_(M) ishalogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, or-L_(S)-R_(E). Also preferably, D is phenyl, and is optionallysubstituted with one or more R_(A). More preferably, D is phenyl, and issubstituted with one or more R_(M), wherein R_(M) is as defined above.Highly preferably, D is

wherein R_(M) is as defined above, and each R_(N) is independentlyselected from R_(D) and preferably is hydrogen. One or more R_(N) canalso preferably be halo such as F.

D is also preferably pyridinyl, pyrimidinyl, or thiazolyl, optionallysubstituted with one or more R_(A). More preferably D is pyridinyl,pyrimidinyl, or thiazolyl, and is substituted with one or more R_(M).Highly preferably, D

is wherein R_(M) is as defined above, and each R_(N) is independentlyselected from R_(D) and preferably is hydrogen. One or more R_(N) canalso preferably be halo such as F. D is also preferably indanyl,4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, or indazolyl,and is optionally substituted with one or more R_(A). More preferably Dis indanyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl,indazolyl, or benzo[d][1,3]dioxol-5-yl, and is substituted with one ormore R_(M). Highly preferably, D is

and is optionally substituted with one or more R_(M).

Preferably, R_(M) is halogen, hydroxy, mercapto, amino, carboxy, nitro,oxo, phosphonoxy, phosphono, thioxo, cyano; or C₁-C₆alkyl, C₂-C₆alkenylor C₂-C₆alkynyl, each of which is independently optionally substitutedat each occurrence with one or more substituents selected from halogen,hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,thioxo, formyl or cyano; or C₃-C₆carbocycle or 3- to 6-memberedheterocycle, each of which is independently optionally substituted ateach occurrence with one or more substituents selected from halogen,hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,thioxo, formyl, cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆haloalkyl, C₂-C₆haloalkenyl or C₂-C₆haloalkynyl. More preferably,R_(M) is halogen, hydroxy, mercapto, amino, carboxy; or C₁-C₆alkyl,C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is independently optionallysubstituted at each occurrence with one or more substituents selectedfrom halogen, hydroxy, mercapto, amino or carboxy. Highly preferably,R_(M) is C₁-C₆alkyl which is independently optionally substituted withone or more substituents selected from halogen, hydroxy, mercapto, aminoor carboxy.

Also preferably, R_(M) is halogen, hydroxy, mercapto, amino, carboxy,nitro, oxo, phosphonoxy, phosphono, thioxo, or cyano; or R_(M) is-L_(S)-R_(E), wherein L_(S) is a bond or C₁-C₆alkylene, and R_(E) is—N(R_(S)R_(S)′), —O—R_(S), —C(O)R_(S), —C(O)OR_(S), —C(O)N(R_(S)R_(S)′),—N(R_(S))C(O)R_(S)′, —N(R_(S))C(O)OR_(S)′, —N(R_(S))SO₂R_(S)′,—SO₂R_(S), —SR_(S), or —P(O)(OR_(S))₂, wherein R_(S) and R_(S)′ can be,for example, each independently selected at each occurrence from (1)hydrogen or (2) C₁-C₆alkyl optionally substituted at each occurrencewith one or more halogen, hydroxy, —O—C₁-C₆alkyl or 3- to 6-memberedheterocycle; or R_(M) is C₁-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl, eachof which is independently optionally substituted at each occurrence withone or more substituents selected from halogen, hydroxy, mercapto,amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl orcyano; or R_(M) is C₃-C₆carbocycle or 3- to 6-membered heterocycle, eachof which is independently optionally substituted at each occurrence withone or more substituents selected from halogen, hydroxy, mercapto,amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl,cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl,C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, —C(O)OR_(S), or —N(R_(S)R_(S)′).More preferably, R_(M) is halogen (e.g., fluoro, chloro, bromo, iodo),hydroxy, mercapto, amino, carboxy, or C₁-C₆alkyl (e.g., methyl,isopropyl, tert-butyl), C₂-C₆alkenyl or C₂-C₆alkynyl, each of which isindependently optionally substituted at each occurrence with one or moresubstituents selected from halogen, hydroxy, mercapto, amino, cyano, orcarboxy. For example R_(M) is CF₃, —C(CF₃)₂—OH, —C(CH₃)₂—CN,—C(CH₃)₂—CH₂OH, or —C(CH₃)₂—CH₂NH₂. Also preferably R_(M) is-L_(S)-R_(E) where L_(S) is a bond and R_(E) is —N(R_(S)R_(S′)),—O—R_(S), —N(R_(S))C(O)OR_(S)′, —N(R_(S))SO₂R_(S)′, —SO₂R_(S), or—SR_(S). For example where L_(S) is a bond, R_(E) is —N(C₁-C₆alkyl)₂(e.g., —NMe₂); —N(C₁-C₆alkylene—O—C₁-C₆alkyl)₂ (e.g. —N(CH₂CH₂OMe)₂);—N(C₁-C₆alkyl)(C₁-C₆alkylene—O—C₁-C₆alkyl) (e.g. —N(CH₃)(CH₂CH₂OMe));—O—C₁-C₆alkyl (e.g., —O-Me, —O-Et, —O-isopropyl, —O-tert-butyl,—O-n-hexyl); —O—C₁-C₆haloalkyl (e.g., —OCF₃, —OCH₂CF₃);—O—C₁-C₆alkylene-piperidine (e.g., —O—CH₂CH₂-1-piperidyl);—N(C₁-C₆alkyl)C(O)OC₁-C₆alkyl (e.g., —N(CH₃)C(O)O—CH₂CH(CH₃)₂),—N(C₁-C₆alkyl)SO₂C₁-C₆alkyl (e.g., —N(CH₃)SO₂CH₃); —SO₂C₁-C₆alkyl (e.g.,—SO₂Me); —SO₂C₁-C₆haloalkyl (e.g., —SO₂CF₃); or —S—C₁-C₆haloalkyl (e.g.,SCF₃). Also preferably R_(M) is -L_(S)-R_(E) where L_(S) isC₁-C₆alkylene (e.g., —CH₂—, —C(CH₃)₂—, —C(CH₃)₂—CH₂—) and R_(E) is—O—R_(S), —C(O)OR_(S), —N(R_(S))C(O)OR_(S)′, or —P(O)(OR_(S))₂. Forexample R_(M) is —C₁-C₆alkylene—O—R_(S) (e.g., —C(CH₃)₂—CH₂—OMe);—C₁-C₆alkylene—C(O)OR_(S) (e.g., —C(CH₃)₂—C(O)OMe);—C₁-C₆alkylene-N(R₅)C(O)OR_(S)′ (e.g., —C(CH₃)₂—CH₂—NHC(O)OCH₃); or—C₁-C₆alkylene-P(O)(OR_(S))₂ (e.g., —CH₂—P(O)(OEt)₂). Also morepreferably R_(M) is C₃-C₆carbocycle or 3- to 6-membered heterocycle,each of which is independently optionally substituted at each occurrencewith one or more substituents selected from halogen, hydroxy, mercapto,amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl,cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl,C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, —C(O)OR_(S), or —N(R_(S)R_(S)′). Forexample R_(M) is cycloalkyl (e.g., cyclopropyl,2,2-dichloro-1-methylcycloprop-1-yl, cyclohexyl), phenyl, heterocyclyl(e.g., morpholin-4-yl, 1,1-dioxidothiomorpholin-4-yl,4-methylpiperazin-1-yl, 4-methoxycarbonylpiperazin-1-yl,pyrrolidin-1-yl, piperidin-1-yl, 4-methylpiperidin-1-yl,3,5-dimethylpiperidin-1-yl, 4,4-difluoropiperidin-1-yl,tetrahydropyran-4-yl, pyridinyl, pyridin-3-yl,6-(dimethylamino)pyridin-3-yl). Highly preferably, R_(M) is C₁-C₆alkylwhich is independently optionally substituted with one or moresubstituents selected from halogen, hydroxy, mercapto, amino or carboxy(e.g., tert-butyl, CF₃).

More preferably, D is C₅-C₆carbocycle, 5- to 6-membered heterocycle or6- to 12-membered bicycle and is substituted with J and optionallysubstituted with one or more R_(A), wherein J is C₃-C₆carbocycle, 3- to6-membered heterocycle or 6- to 12-membered bicycle and is optionallysubstituted with one or more R_(A). Preferably, J is substituted with aC₃-C₆carbocycle or 3- to 6-membered heterocycle, wherein saidC₃-C₆carbocycle or 3- to 6-membered heterocycle is independentlyoptionally substituted with one or more substituents selected fromhalogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy,phosphono, thioxo, formyl, cyano, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₁-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl,C(O)OR_(S) or —N(R_(S)R_(S)′), and J can also be optionally substitutedwith one or more R_(A). Also preferably, D is C₅-C₆carbocycle or 5- to6-membered heterocycle and is substituted with J and optionallysubstituted with one or more R_(A), and J is C₃-C₆carbocycle or 3- to6-membered heterocycle and is optionally substituted with one or moreR_(A), and preferably, J is at least substituted with a C₃-C₆carbocycleor 3- to 6-membered heterocycle which is independently optionallysubstituted with one or more substituents selected from halogen,hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,thioxo, formyl, cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, C(O)OR_(S) or—N(R_(S)R_(S)′). Also preferably, D is C₅-C₆carbocycle or 5- to6-membered heterocycle and is substituted with J and optionallysubstituted with one or more R_(A), and J is 6- to 12-membered bicycle(e.g., a 7- to 12-membered fused, bridged or spiro bicycle comprising anitrogen ring atom through which J is covalently attached to D) and isoptionally substituted with one or more R_(A). More preferably, D isphenyl and is substituted with J and optionally substituted with one ormore R_(A), and J is C₃-C₆carbocycle, 3- to 6-membered heterocycle or 6-to 12-membered bicycle and is optionally substituted with one or moreR_(A), and preferably J is at least substituted with a C₃-C₆carbocycleor 3- to 6-membered heterocycle which is independently optionallysubstituted with one or more substituents selected from halogen,hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,thioxo, formyl, cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, C(O)OR_(S) or—N(R_(S)R_(S)′). Highly preferably, D is

wherein each R_(N) is independently selected from R_(D) and preferablyis hydrogen or halogen, and J is C₃-C₆carbocycle, 3- to 6-memberedheterocycle or 6- to 12-membered bicycle and is optionally substitutedwith one or more R_(A), and preferably J is at least substituted with aC₃-C₆carbocycle or 3- to 6-membered heterocycle which is independentlyoptionally substituted with one or more substituents selected fromhalogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy,phosphono, thioxo, formyl, cyano, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₁-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl,C(O)OR_(S) or —N(R_(S)R_(S)′). Also preferably, D is

wherein each R_(N) is independently selected from R_(D) and preferablyis hydrogen or halogen, and J is C₃-C₆carbocycle or 3- to 6-memberedheterocycle and is substituted with a C₃-C₆carbocycle or 3- to6-membered heterocycle which is independently optionally substitutedwith one or more substituents selected from halogen, hydroxy, mercapto,amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl,cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl,C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, C(O)OR_(S) or —N(R_(S)R_(S)′), and Jcan also be optionally substituted with one or more R_(A). Alsopreferably, D is

and J is C₃-C₆carbocycle or 3- to 6-membered heterocycle and isoptionally substituted with one or more R_(A), and preferably J is atleast substituted with a C₃-C₆carbocycle or 3- to 6-membered heterocyclewhich is independently optionally substituted with one or moresubstituents selected from halogen, hydroxy, mercapto, amino, carboxy,nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl, C₂-C₆haloalkenyl,C₂-C₆haloalkynyl, C(O)OR_(S) or —N(R_(S)R_(S)′).

X preferably is C₅-C₆carbocycle, 5- to 6-membered heterocycle, or 6- to12-membered bicycles (e.g.,

wherein X₃ is N and is directly linked to -L₃-D), and is optionallysubstituted with one or more R_(A) or R. Non-limiting examples of X aredescribed hereinabove.

L₁ and L₂ are preferably independently bond or C₁-C₆alkylene, L₃ ispreferably selected from bond, C₁-C₆alkylene or —C(O)—, and L₁, L₂, andL₃ are each independently optionally substituted with one or more R_(L).More preferably, L₁, L₂ and L₃ are each independently bond orC₁-C₆alkylene (e.g., —CH₂— or —CH₂CH₂—), and are each independentlyoptionally substituted with one or more R_(L). Highly preferably, L₁, L₂and L₃ are bond.

R₂ and R₅, taken together with the atoms to which they are attached,preferably form a 5- to 6-membered heterocycle or 6- to 12-memberedbicycle (e.g.,

which is optionally substituted with one or more R_(A).

R₉ and R₁₂, taken together with the atoms to which they are attached,preferably form a 5- to 6-membered heterocycle or 6- to 12-memberedbicycle (e.g.,

which is optionally substituted with one or more R_(A).

-T-R_(D)′ can be, without limitation, independently selected at eachoccurrence from —C(O)-L_(T)′—, —C(O)O-L_(Y)′—R_(D)′,—C(O)-L_(Y)′—N(R_(B))C(O)-L_(S)″—R_(D)′,—C(O)-L_(Y)′—N(R_(B))C(O)O-L_(S)″—R_(D)′,—N(R_(B))C(O)-L_(Y)′—N(R_(B))C(O)-L_(S)″—R_(D)′,—N(R_(B))C(O)-L_(Y)′—N(R_(B))C(O)O-L_(S)″—R_(D)′, or—N(R_(B))C(O)-L_(Y)′—N(R_(B))-L_(S)″—R_(D)′, wherein L_(Y)′ is eachindependently L_(S)′ and, preferably, is each independentlyC₁-C₆alkylene (e.g., —CH₂— or

and optionally substituted with one or more substituents selected fromR_(L). Preferably, -T-R_(D)′ is independently selected at eachoccurrence from —C(O)-L_(Y)′— M′-L_(S)″—R_(D)′ or—N(R_(B))C(O)-L_(Y)′-M′-L_(S)″—R_(D)′. More preferably, -T-R_(D)′ isindependently selected at each occurrence from—C(O)-L_(Y)′—N(R_(B))C(O)-L_(S)″—R_(D)′ or—C(O)-L_(Y)′—N(R_(B))C(O)O-L_(S)″—R_(D)′. Highly preferably, -T-R_(D)′is independently selected at each occurrence from—C(O)-L_(T)′—N(R_(B))C(O)—R_(D)′ or —C(O)-L_(Y)′—N(R_(B))C(O)O—R_(D)′,wherein L_(Y)′ preferably is each independently C₁-C₆alkylene (e.g.,—CH₂— or

and optionally substituted with one or more substituents selected fromR_(L).

R_(NB) and R_(C)′ are preferably hydrogen, and R_(D)′ preferably isindependently selected at each occurrence from R_(E). More preferably,R_(D)′ is independently selected at each occurrence from C_(r) C₆alkyl,C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is independently optionallysubstituted at each occurrence with one or more substituents selectedfrom halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,phosphonoxy, phosphono, thioxo, formyl, cyano, C₃-C₆carbocycle or 3- to6-membered heterocycle; or C₃-C₆carbocycle or 3- to 6-memberedheterocycle, each of which is independently optionally substituted ateach occurrence with one or more substituents selected from halogen,hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,thioxo, formyl, cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆haloalkyl, C₂-C₆haloalkenyl or C₂-C₆haloalkynyl.

R_(A) preferably is halogen, hydroxy, mercapto, amino, carboxy, nitro,oxo, phosphonoxy, phosphono, thioxo, cyano; or C₁-C₆alkyl, C₂-C₆alkenylor C₂-C₆alkynyl, each of which is independently optionally substitutedat each occurrence with one or more substituents selected from halogen,hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,thioxo, formyl or cyano; or C₃-C₆carbocycle or 3- to 6-memberedheterocycle, each of which is independently optionally substituted ateach occurrence with one or more substituents selected from halogen,hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,thioxo, formyl, cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆haloalkyl, C₂-C₆haloalkenyl or C₂-C₆haloalkynyl; or -L_(A)-O—R_(S),-L_(A)-S—R_(S), -L_(A)-C(O)R_(S), -L_(A)-OC(O)R_(S), -L_(A)-C(O)OR_(S),-L_(A)-N(R_(S)R_(S)′), -L_(A)-S(O)R_(S), -L_(A)-SO₂R_(S),-L_(A)-C(O)N(R_(S)R_(S)′), -L_(A)-N(R_(S))C(O)R_(S)′,-L_(A)-N(R_(S))C(O)N(R_(S)′R_(S)″), -L_(A)-N(R_(S))SO₂R_(S)′,-L_(A)-SO₂N(R_(S)R_(S)′), -L_(A)-N(R_(S))SO₂N(R_(S)′R_(S)″),-L_(A)-N(R_(S))S(O)N(R_(S)′R_(S)″), -L_(A)-OS(O)—R_(S),-L_(A)-OS(O)₂—R_(S), -L_(A)-S(O)₂OR_(S), -L_(A)-S(O)OR_(S),-L_(A)-OC(O)OR_(S), -L_(A)-N(R_(S))C(O)OR_(S)′,-L_(A)-OC(O)N(R_(S)R_(S)′), -L_(A)-N(R_(S))S(O)—R_(S)′,-L_(A)-S(O)N(R_(S)R_(S)′) or -L_(A)-C(O)N(R_(S))C(O)—R_(S)′, whereinL_(A) is bond, C₁-C₆alkylene, C₂-C₆alkenylene or C₂-C₆alkynylene.

More preferably, R_(A) is halogen, hydroxy, mercapto, amino, carboxy,nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or C₁-C₆alkyl,C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is independently optionallysubstituted at each occurrence with one or more substituents selectedfrom halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,phosphonoxy, phosphono, thioxo, formyl or cyano; or C₃-C₆carbocycle or3- to 6-membered heterocycle, each of which is independently optionallysubstituted at each occurrence with one or more substituents selectedfrom halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,phosphonoxy, phosphono, thioxo, formyl, cyano, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₁-C₆haloalkyl, C₂-C₆haloalkenyl or C₂-C₆haloalkynyl.

Highly preferably, R_(A) is halogen, hydroxy, mercapto, amino, carboxy,nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or C₁-C₆alkyl,C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is independently optionallysubstituted at each occurrence with one or more substituents selectedfrom halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,phosphonoxy, phosphono, thioxo, formyl or cyano.

L_(S), L_(S)′ and L_(S)″ preferably are each independently selected ateach occurrence from bond; or C₁-C₆alkylene, C₂-C₆alkenylene orC₂-C₆alkynylene.

A and B can be the same or different. Likewise, L₁ and L₂ can be thesame or different.

In one embodiment of this aspect, A and B are each independently phenyl,and are each independently optionally substituted with one or moreR_(A); D is phenyl, and is optionally substituted with one or moreR_(A), or is substituted with J and optionally substituted with one ormore R_(A), wherein J is C₃-C₆carbocycle, 3- to 6-membered heterocycleor 6- to 12-membered bicycle and is optionally substituted with one ormore R_(A). Preferably, J is substituted with a C₃-C₆carbocycle or 3- to6-membered heterocycle which is independently optionally substitutedwith one or more substituents selected from halogen, hydroxy, mercapto,amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl,cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl,C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, C(O)OR_(S) or —N(R_(S)R_(S)′), and Jcan also be optionally substituted with one or more R_(A). Preferably, Dis

wherein R_(M) and R_(N) are as defined above. Also preferably, D is

wherein J and R_(N) are as defined above. L₁ and L₂ are eachindependently bond or C₁-C₆alkylene, and L₃ is bond, C₁-C₆alkylene or—C(O)—, and L₁, L₂, and L₃ are each independently optionally substitutedwith one or more R_(L). Preferably, L₁, L₂, and L₃ are bond. -T-R_(D)′is independently selected at each occurrence from—C(O)-L_(Y)′—N(R_(B))C(O)-L_(S)″—R_(D)′ or—C(O)-L_(Y)′—N(R_(B))C(O)O-L_(S)″—R_(D)′, wherein L_(Y)′ isC₁-C₆alkylene (e.g., —CH₂—) and optionally substituted with one or moresubstituents selected from R_(L), and L_(S)″ preferably is bond.-T-R_(D)′ can also be, without limitation, selected from—C(O)-L_(Y)-L_(S)″—R_(D)′, —C(O)-L_(Y)′—O-L_(S)″—R_(D)′,—C(O)-L_(Y)′—N(R_(B)) L_(S)″—R_(D)′, or—C(O)-L_(Y)′—N(R_(B))S(O)₂-L_(S)″—R_(D)′. Preferably, R₂ and R₅, takentogether with the atoms to which they are attached, form

which is optionally substituted with one or more R_(A); R₉ and R₁₂,taken together with the atoms to which they are attached, form

which is optionally substituted with one or more R_(A).

In another embodiment of this aspect, A and B are each independentlyphenyl (e.g.,

and are each independently optionally substituted with one or more R_(A)(preferably, A and B are each independently substituted with at leastone halo such as F). X is

wherein X₃ is N and is directly linked to -L₃-D, and X is optionallysubstituted with one or more R_(A) or R_(F). D is phenyl, and issubstituted with J and optionally substituted with one or more R_(A). Jis C₃-C₆carbocycle, 3- to 6-membered heterocycle, 6- to 12-memberedbicycle, 10- to 15-membered tricycle or 13- to 15-memberedcarbocycle/heterocycle, and J is optionally substituted with one or moreR_(A). Preferably, J is substituted with a C₃-C₆carbocycle, 3- to6-membered heterocycle, 6- to 12-membered bicycle or 7- to 12-memberedcarbocycle/heterocycle, which is independently optionally substitutedwith one or more substituents selected from (1) halogen, hydroxy,mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo,formyl, cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl,C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, —C(O)OR_(S) or —N(R_(S)R_(S)′), or(2) trimethylsilyl, —O—R_(S), —S—R_(S) or —C(O)R_(S); and J can also beoptionally substituted with one or more R_(A). Preferably, D is

wherein J is as defined above, and each R_(N) is independently selectedfrom R_(D) and preferably is hydrogen or halo such as F. L₁ and L₂ areeach independently bond or C₁-C₆alkylene, and L₃ is bond, C₁-C₆alkyleneor —C(O)—, and L₁, L₂, and L₃ are each independently optionallysubstituted with one or more R_(L). Preferably, L₁, L₂, and L₃ are bond.-T-R_(D)′ is independently selected at each occurrence from—C(O)-L_(Y)′—N(R_(B))C(O)-L_(S)″—R_(D)′ or—C(O)-L_(Y)′—N(R_(B))C(O)O-L_(S)″—R_(D)′, wherein L_(Y)′ isC₁-C₆alkylene (e.g., —CH₂—) and optionally substituted with one or moresubstituents selected from R_(L), and L_(S)″ preferably is bond.-T-R_(D)′ can also be, without limitation, selected from—C(O)-L_(Y)′-L_(S)″—R_(D)′, —C(O)-L_(Y)′—O-L_(S)″—R_(D)′,—C(O)-L_(Y)′—N(R_(a))-L_(S)″—R_(D)′, or—C(O)-L_(Y)′—N(R_(B))S(O)₂-L_(S)″—R_(D)′. R₂ and R₅, taken together withthe atoms to which they are attached, form a 5- to 6-memberedheterocyclic ring (e.g.,

or 6- to 12-membered bicycle (e.g.,

which is optionally substituted with one or more R_(A); and R₉ and R₁₂,taken together with the atoms to which they are attached, form a 5- to6-membered heterocyclic ring (e.g.,

or 6- to 12-membered bicycle (e.g.,

which is optionally substituted with one or more R_(A).

In still another aspect, the present invention features compounds ofFormula I_(B) and pharmaceutically acceptable salts thereof:

wherein:

-   -   R_(C)′ is each independently selected from R_(C);    -   R_(D)′ is each independently selected from R_(D);    -   R₂ and R₅, taken together with the atoms to which they are        attached, form a 3- to 12-membered heterocycle which is        optionally substituted with one or more R_(A);    -   R₉ and R₁₂, taken together with the atoms to which they are        attached, form a 3- to 12-membered heterocycle which is        optionally substituted with one or more R_(A);    -   A, B, D, X, L₁, L₂, L₃, T, R_(A), R_(C), and R_(D) are as        described above in Formula I.

In this aspect, A and B preferably are independently selected from 8- to12-membered bicycles such as

where Z₁ is independently selected at each occurrence from O, S, NH orCH₂, Z₂ is independently selected at each occurrence from N or CH, Z₃ isindependently selected at each occurrence from N or CH, Z₄ isindependently selected at each occurrence from O, S, NH or CH₂, and W₁;W₂, W₃, W₄, W₅ and W₆ are each independently selected at each occurrencefrom CH or N. A and B are each independently optionally substituted withone or more R_(A).

More preferably, A is selected from

and is optionally substituted with one or more R_(A); B is selected from

and is optionally substituted with one or more R_(A), where Z₁, Z₂, Z₃,Z₄, W₁, W₂, W₃, W₄, W_(S), W₆ are as defined above. Preferably, Z₃ is Nand Z₄ is NH. For instance, A can be selected from

(e.g.,

(e.g.,

and is optionally substituted with one or more R_(A); and B can beselected from

(e.g.,

(e.g.,

and is optionally substituted with one or more R_(A).

Also preferably, A is

(e.g.,

and B is

(e.g.,

wherein A′ and B′ are independently selected from C₅-C₆carbocycle or 5-to 6-membered heterocycle, and A and B are independently optionallysubstituted with one or more R_(A).

More preferably, A is

B is

and A and B are substituted with one or more halogen, such as F or Cl.When A and/or B are halo-substituted benzimidazole (e.g., A is

and B is

the compounds of Formula I_(B) can have significantly improvedpharmacokinetic properties as well as improved inhibitory activityagainst certain HCV genotype 1a mutants, as compared to the samecompounds but with unsubstituted benzimidazole.

D preferably is selected from C₅-C₆carbocycle, 5- to 6-memberedheterocycle, or 6- to 12-membered bicycles, and is optionallysubstituted with one or more R_(A). D can also be preferably selectedfrom C₁-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl, and is optionallysubstituted with one or more substituents selected from R_(L). Morepreferably, D is C₅-C₆carbocycle, 5- to 6-membered heterocycle, or 6- to12-membered bicycles, and is substituted with one or more R_(M), whereR_(M) is halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, or-L_(S)-R_(E). Also preferably, D is phenyl, and is optionallysubstituted with one or more R_(A). More preferably, D is phenyl, and issubstituted with one or more R_(M), wherein R_(M) is as defined above.Highly preferably, D is

wherein R_(M) is as defined above, and each R_(N) is independentlyselected from R_(D) and preferably is hydrogen. One or more R_(N) canalso preferably be halo such as F.

D is also preferably pyridinyl, pyrimidinyl, or thiazolyl, optionallysubstituted with one or more R_(A). More preferably D is pyridinyl,pyrimidinyl, or thiazolyl, and is substituted with one or more R_(M).Highly preferably, D is

wherein R_(M) is as defined above, and each R_(N) is independentlyselected from R_(D) and preferably is hydrogen. One or more R_(N) canalso preferably be halo such as F. D is also preferably indanyl,4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, or indazolyl,and is optionally substituted with one or more R_(A). More preferably Dis indanyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl,indazolyl, or benzo[d][1,3]dioxol-5-yl, and is substituted with one ormore R_(M). Highly preferably, D is

and is optionally substituted with one or more R_(M).

Preferably, R_(M) is halogen, hydroxy, mercapto, amino, carboxy, nitro,oxo, phosphonoxy, phosphono, thioxo, cyano; or C₁-C₆alkyl, C₂-C₆alkenylor C₂-C₆alkynyl, each of which is independently optionally substitutedat each occurrence with one or more substituents selected from halogen,hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,thioxo, formyl or cyano; or C₃-C₆carbocycle or 3- to 6-memberedheterocycle, each of which is independently optionally substituted ateach occurrence with one or more substituents selected from halogen,hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,thioxo, formyl, cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆haloalkyl, C₂-C₆haloalkenyl or C₂-C₆haloalkynyl. More preferably,R_(M) is halogen, hydroxy, mercapto, amino, carboxy; or C₁-C₆alkyl,C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is independently optionallysubstituted at each occurrence with one or more substituents selectedfrom halogen, hydroxy, mercapto, amino or carboxy. Highly preferably,R_(M) is C₁-C₆alkyl which is optionally substituted with a one or moresubstituents selected from halogen, hydroxy, mercapto, amino or carboxy.

Also preferably, R_(M) is halogen, hydroxy, mercapto, amino, carboxy,nitro, oxo, phosphonoxy, phosphono, thioxo, or cyano; or R_(M) is-L_(S)-R_(E), wherein L_(S) is a bond or C₁-C₆alkylene, and R_(E) is—N(R_(S)R_(S)′), —O—R_(S), —C(O)R_(S), —C(O)OR_(S), —C(O)N(R_(S)R_(S)′),—N(R_(S))C(O)R_(S)′, —N(R_(S))C(O)OR_(S)′, —N(R_(S))SO₂R_(S)′,—SO₂R_(S), —SR_(S), or —P(O)(OR_(S))₂, wherein R_(S) and R_(S)′ can be,for example, each independently selected at each occurrence from (1)hydrogen or (2) C₁-C₆alkyl optionally substituted at each occurrencewith one or more halogen, hydroxy, —O—C₁-C₆alkyl or 3- to 6-memberedheterocycle; or R_(M) is C₁-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl, eachof which is independently optionally substituted at each occurrence withone or more substituents selected from halogen, hydroxy, mercapto,amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl orcyano; or R_(M) is C₃-C₆carbocycle or 3- to 6-membered heterocycle, eachof which is independently optionally substituted at each occurrence withone or more substituents selected from halogen, hydroxy, mercapto,amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl,cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl,C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, —C(O)OR_(S), or —N(R_(S)R_(S)′).More preferably, R_(M) is halogen (e.g., fluoro, chloro, bromo, iodo),hydroxy, mercapto, amino, carboxy, or C₁-C₆alkyl (e.g., methyl,isopropyl, tert-butyl), C₂-C₆alkenyl or C₂-C₆alkynyl, each of which isindependently optionally substituted at each occurrence with one or moresubstituents selected from halogen, hydroxy, mercapto, amino, cyano, orcarboxy. For example R_(M) is CF₃, —C(CF₃)₂—OH, —C(CH₃)₂—CN,—C(CH₃)₂—CH₂OH, or —C(CH₃)₂—CH₂NH₂. Also preferably R_(M) is-L_(S)-R_(E) where L_(S) is a bond and R_(E) is —N(R_(S)R_(S′)),—O—R_(S), —N(R_(S))C(O)OR_(S)′, —N(R_(S))SO₂R_(S)′, —SO₂R_(S), or—SR_(S). For example where L_(S) is a bond, R_(E) is —N(C₁-C₆alkyl)₂(e.g., —NMe₂); —N(C₁-C₆alkylene—O—C₁-C₆alkyl)₂ (e.g. —N(CH₂CH₂OMe)₂);—N(C₁-C₆alkyl)(C₁-C₆alkylene—O—C₁-C₆alkyl) (e.g. —N(CH₃)(CH₂CH₂OMe)); 0C₁-C₆alkyl (e.g., —O-Me, —O-Et, —O-isopropyl, —O-tert-butyl,—O-n-hexyl); —O—C₁-C₆haloalkyl (e.g., —OCF₃, —OCH₂CF₃);—O—C₁-C₆alkylene-piperidine (e.g., —O—CH₂CH₂-1-piperidyl);—N(C₁-C₆alkyl)C(O)OC₁-C₆alkyl (e.g., —N(CH₃)C(O)O—CH₂CH(CH₃)₂),—N(C₁-C₆alkyl)SO₂C₁-C₆alkyl (e.g., —N(CH₃)SO₂CH₃); —SO₂C₁-C₆alkyl (e.g.,—SO₂Me); —SO₂C₁-C₆haloalkyl (e.g., —SO₂CF₃); or —S—C₁-C₆haloalkyl (e.g.,SCF₃). Also preferably R_(M) is -L_(S)-R_(E) where L_(S) isC₁-C₆alkylene (e.g., —CH₂—, —C(CH₃)₂—, —C(CH₃)₂—CH₂—) and R_(E) is—O—R_(S), —C(O)OR_(S), —N(R_(S))C(O)OR_(S)′, or —P(O)(OR_(S))₂. Forexample R_(M) is —C₁-C₆alkylene—O—R_(S) (e.g., —C(CH₃)₂—CH₂-OMe);—C₁-C₆alkylene—C(O)OR_(S) (e.g., —C(CH₃)₂—C(O)OMe);—C₁-C₆alkylene—N(R_(S))C(O)OR_(S)′ (e.g., —C(CH₃)₂—CH₂—NHC(O)OCH₃); or—C₁-C₆alkylene—P(O)(OR_(S))₂ (e.g., —CH₂—P(O)(OEt)₂). Also morepreferably R_(M) is C₃-C₆carbocycle or 3- to 6-membered heterocycle,each of which is independently optionally substituted at each occurrencewith one or more substituents selected from halogen, hydroxy, mercapto,amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl,cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl,C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, —C(O)OR_(S), or —N(R_(S)R_(S)′). Forexample R_(M) is cycloalkyl (e.g., cyclopropyl,2,2-dichloro-1-methylcycloprop-1-yl, cyclohexyl), phenyl, heterocyclyl(e.g., morpholin-4-yl, 1,1-dioxidothiomorpholin-4-yl,4-methylpiperazin-1-yl, 4-methoxycarbonylpiperazin-1-yl,pyrrolidin-1-yl, piperidin-1-yl, 4-methylpiperidin-1-yl,3,5-dimethylpiperidin-1-yl, 4,4-difluoropiperidin-1-yl,tetrahydropyran-4-yl, pyridinyl, pyridin-3-yl,6-(dimethylamino)pyridin-3-yl). Highly preferably, R_(M) is C₁-C₆alkylwhich is optionally substituted with one or more substituents selectedfrom halogen, hydroxy, mercapto, amino or carboxy (e.g., tert-butyl,CF₃).

More preferably, D is C₅-C₆carbocycle, 5- to 6-membered heterocycle or6- to 12-membered bicycle and is substituted with J and optionallysubstituted with one or more R_(A), wherein J is C₃-C₆carbocycle, 3- to6-membered heterocycle or 6- to 12-membered bicycle and is optionallysubstituted with one or more R_(A). Preferably, J is substituted with aC₃-C₆carbocycle or 3- to 6-membered heterocycle, wherein saidC₃-C₆carbocycle or 3- to 6-membered heterocycle is independentlyoptionally substituted with one or more substituents selected fromhalogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy,phosphono, thioxo, formyl, cyano, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₁-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl,C(O)OR_(S) or —N(R_(S)R_(S)′), and J can also be optionally substitutedwith one or more R_(A). Also preferably, D is C₅-C₆carbocycle or 5- to6-membered heterocycle and is substituted with J and optionallysubstituted with one or more R_(A), and J is C₃-C₆carbocycle or 3- to6-membered heterocycle and is optionally substituted with one or moreR_(A), and preferably, J is at least substituted with a C₃-C₆carbocycleor 3- to 6-membered heterocycle which is independently optionallysubstituted with one or more substituents selected from halogen,hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,thioxo, formyl, cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, C(O)OR_(S) or—N(R_(S)R_(S)′). Also preferably, D is C₅-C₆carbocycle or 5- to6-membered heterocycle and is substituted with J and optionallysubstituted with one or more R_(A), and J is 6- to 12-membered bicycle(e.g., a 7- to 12-membered fused, bridged or spiro bicycle comprising anitrogen ring atom through which J is covalently attached to D) and isoptionally substituted with one or more R_(A). More preferably, D isphenyl and is substituted with J and optionally substituted with one ormore R_(A), and J is C₃-C₆carbocycle, 3- to 6-membered heterocycle or 6-to 12-membered bicycle and is optionally substituted with one or moreR_(A), and preferably J is at least substituted with a C₃-C₆carbocycleor 3- to 6-membered heterocycle which is independently optionallysubstituted with one or more substituents selected from halogen,hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,thioxo, formyl, cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, C(O)OR_(S) or—N(R_(S)R_(S)′). Highly preferably, D is

wherein each R_(N) is independently selected from R_(D) and preferablyis hydrogen or halogen, and J is C₃-C₆carbocycle, 3- to 6-memberedheterocycle or 6- to 12-membered bicycle and is optionally substitutedwith one or more R_(A), and preferably J is at least substituted with aC₃-C₆carbocycle or 3- to 6-membered heterocycle which is independentlyoptionally substituted with one or more substituents selected fromhalogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy,phosphono, thioxo, formyl, cyano, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₁-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl,C(O)OR_(S) or —N(R_(S)R_(S)′). Also preferably, D is

wherein each R_(N) is independently selected from R_(D) and preferablyis hydrogen or halogen, and J is C₃-C₆carbocycle or 3- to 6-memberedheterocycle and is substituted with a C₃-C₆carbocycle or 3- to6-membered heterocycle which is independently optionally substitutedwith one or more substituents selected from halogen, hydroxy, mercapto,amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl,cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl,C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, C(O)OR_(S) or —N(R_(S)R_(S)′), and Jcan also be optionally substituted with one or more R_(A). Alsopreferably, D is

and J is C₃-C₆carbocycle or 3- to 6-membered heterocycle and isoptionally substituted with one or more R_(A), and preferably J is atleast substituted with a C₃-C₆carbocycle or 3- to 6-membered heterocyclewhich is independently optionally substituted with one or moresubstituents selected from halogen, hydroxy, mercapto, amino, carboxy,nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl, C₂-C₆haloalkenyl,C₂-C₆haloalkynyl, C(O)OR_(S) or —N(R_(S)R_(S)′).

X preferably is C₅-C₆carbocycle, 5- to 6-membered heterocycle, or 6- to12-membered bicycles (e.g.,

wherein X₃ is N and is directly linked to -L₃-D), and is optionallysubstituted with one or more R_(A) or R_(F). Non-limiting examples of Xare described hereinabove.

L₁ and L₂ are preferably independently bond or C₁-C₆alkylene, L₃ ispreferably selected from bond, C₁-C₆alkylene or —C(O)—, and L₁, L₂, andL₃ are each independently optionally substituted with one or more R_(L).More preferably, L₁, L₂ and L₃ are each independently bond orC₁-C₆alkylene (e.g., —CH₂— or —CH₂CH₂—), and are each independentlyoptionally substituted with one or more R_(L). Highly preferably, L₁, L₂and L₃ are bond.

R₂ and R₅, taken together with the atoms to which they are attached,preferably form a 5- to 6-membered heterocycle or 6- to 12-memberedbicycle (e.g.,

which is optionally substituted with one or more R_(A). R₉ and R₁₂,taken together with the atoms to which they are attached, preferablyform a 5- to 6-membered heterocycle or 6- to 12-membered bicycle (e.g.,

which is optionally substituted with one or more R_(A).

-T-R_(D)′ can be, without limitation, independently selected at eachoccurrence from —C(O)-L_(Y)′—R_(D)′, —C(O)O-L_(Y)′—R_(D)′,—C(O)-L_(Y)′—N(R_(B))C(O)-L_(S)″—R_(D)′,—C(O)-L_(Y)′—N(R_(B))C(O)O-L_(S)″—R_(D)′,—N(R_(B))C(O)-L_(Y)′—N(R_(B))C(O)-L_(S)″—R_(D)′,—N(R_(B))C(O)-L_(Y)′—N(R_(B))C(O)O-L_(S)″—R_(D)′, or—N(R_(B))C(O)-L_(Y)′—N(R_(B))-L_(S)″—R_(D)′, wherein L_(Y)′ is eachindependently L_(S)′ and, preferably, is each independentlyC₁-C₆alkylene (e.g., —CH₂— or

and optionally substituted with one or more substituents selected fromR_(L). Preferably, -T-R_(D)′ is independently selected at eachoccurrence from —C(O)-L_(Y)′— M′-L_(S)″—R_(D)′ or—N(R_(B))C(O)-L_(Y)′-M′-L_(S)″—R_(D)′. More preferably, -T-R_(D)′ isindependently selected at each occurrence from—C(O)-L_(Y)′—N(R_(B))C(O)-L_(S)″—R_(D)′ or—C(O)-L_(Y)′—N(R_(B))C(O)O-L_(S)″—R_(D)′. Highly preferably, -T-R_(D)′is independently selected at each occurrence from—C(O)-L_(Y)′—N(R_(B))C(O)—R_(D)′ or —C(O)-L_(Y)′—N(R_(B))C(O)O—R_(D)′,wherein L_(Y)′ preferably is each independently C₁-C₆alkylene (e.g.,—CH₂— or

and optionally substituted with one or more substituents selected fromR_(L).

R_(C)′ is preferably hydrogen, and R_(D)′ preferably is independentlyselected at each occurrence from R_(E). More preferably, R_(D)′ isindependently selected at each occurrence from C₁-C₆alkyl, C₂-C₆alkenylor C₂-C₆alkynyl, each of which is independently optionally substitutedat each occurrence with one or more substituents selected from halogen,hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,thioxo, formyl, cyano, C₃-C₆carbocycle or 3- to 6-membered heterocycle;or C₃-C₆carbocycle or 3- to 6-membered heterocycle, each of which isindependently optionally substituted at each occurrence with one or moresubstituents selected from halogen, hydroxy, mercapto, amino, carboxy,nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl, C₂-C₆haloalkenyl orC₂-C₆haloalkynyl.

R_(A) preferably is halogen, hydroxy, mercapto, amino, carboxy, nitro,oxo, phosphonoxy, phosphono, thioxo, cyano; or C₁-C₆alkyl, C₂-C₆alkenylor C₂-C₆alkynyl, each of which is independently optionally substitutedat each occurrence with one or more substituents selected from halogen,hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,thioxo, formyl or cyano; or C₃-C₆carbocycle or 3- to 6-memberedheterocycle, each of which is independently optionally substituted ateach occurrence with one or more substituents selected from halogen,hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,thioxo, formyl, cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆haloalkyl, C₂-C₆haloalkenyl or C₂-C₆haloalkynyl; or -L_(A)-O—R_(S),-L_(A)-S—R_(S), -L_(A)-C(O)R_(S), -L_(A)-OC(O)R_(S), -L_(A)-C(O)OR_(S),-L_(A)-N(R_(S)R_(S)′)—, -L_(A)-S(O)R_(S), -L_(A)-SO₂R_(S),-L_(A)-C(O)N(R_(S)R_(S)′), -L_(A)-N(R_(S))C(O)R_(S)′,-L_(A)-N(R_(S))C(O)N(R_(S)′R_(S)″), -L_(A)-N(R_(S))SO₂R_(S)′,-L_(A)-SO₂N(R_(S)R_(S)′), -L_(A)-N(R_(S))SO₂N(R_(S)′R_(S)″),-L_(A)-N(R_(S))S(O)N(R_(S)′R_(S)″), -L_(A)-OS(O)—R_(S),-L_(A)-OS(O)₂—R₅, -L_(A)-S(O)₂OR_(S), -L_(A)-S(O)OR_(S),-L_(A)-OC(O)OR_(S), -L_(A)-N(R_(S))C(O)OR_(S)′,-L_(A)-OC(O)N(R_(S)R_(S)′), -L_(A)-N(R_(S))S(O)—R_(S)′,-L_(A)-S(O)N(R_(S)R_(S)′) or -L_(A)-C(O)N(R_(S))C(O)—R_(S)′, whereinL_(A) is bond, C₁-C₆alkylene, C₂-C₆alkenylene or C₂-C₆alkynylene.

More preferably, R_(A) is halogen, hydroxy, mercapto, amino, carboxy,nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or C₁-C₆alkyl,C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is independently optionallysubstituted at each occurrence with one or more substituents selectedfrom halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,phosphonoxy, phosphono, thioxo, formyl or cyano; or C₃-C₆carbocycle or3- to 6-membered heterocycle, each of which is independently optionallysubstituted at each occurrence with one or more substituents selectedfrom halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,phosphonoxy, phosphono, thioxo, formyl, cyano, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₁-C₆haloalkyl, C₂-C₆haloalkenyl or C₂-C₆haloalkynyl.

Highly preferably, R_(A) is halogen, hydroxy, mercapto, amino, carboxy,nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or C₁-C₆alkyl,C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is independently optionallysubstituted at each occurrence with one or more substituents selectedfrom halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,phosphonoxy, phosphono, thioxo, formyl or cyano.

L_(S), L_(S)′ and L_(S)″ preferably are each independently selected ateach occurrence from bond; or C₁-C₆alkylene, C₂-C₆alkenylene orC₂-C₆alkynylene.

A and B can be the same or different. Likewise, L₁ and L₂ can be thesame or different.

In one embodiment of this aspect, A is

and is optionally substituted with one or more R_(A); B is

and is optionally substituted with one or more R_(A); and D isC₅-C₆carbocycle or 5- to 6-membered heterocycle (e.g., phenyl), and isoptionally substituted with one or more R_(A), or is substituted with Jand optionally substituted with one or more R_(A), wherein J isC₃-C₆carbocycle, 3- to 6-membered heterocycle or 6- to 12-memberedbicycle and is optionally substituted with one or more R_(A).Preferably, J is substituted with a C₃-C₆carbocycle or 3- to 6-memberedheterocycle which is independently optionally substituted with one ormore substituents selected from halogen, hydroxy, mercapto, amino,carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano,C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl,C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, C(O)OR_(S) or —N(R_(S)R_(S)′), and Jcan also be optionally substituted with one or more R_(A). Preferably, Dis

wherein R_(M) and R_(N) are as defined above. Also preferably, D is

wherein J and R_(N) are as defined above. Z₁ is independently selectedat each occurrence from O, S, NH or CH₂; and Z₂ is independentlyselected at each occurrence from N or CH. Preferably, A is

B is

and A and B are substituted with one or more halogen, such as F or Cl.When A and/or B are halo-substituted benzimidazole (e.g., A is

and B is

the compounds of this embodiment can have significantly improvedpharmacokinetic properties as well as improved inhibitory activityagainst certain HCV genotype 1a mutants, as compared to the samecompounds but with unsubstituted benzimidazole. L₁ and L₂ are eachindependently bond or C₁-C₆alkylene, and L₃ is bond, C₁-C₆alkylene or—C(O)—, and L₁, L₂, and L₃ are each independently optionally substitutedwith one or more R_(L). Preferably, L₁, L₂, and L₃ are bond. -T-R_(D)′is independently selected at each occurrence from—C(O)-L_(Y)′—N(R_(B))C(O)-L_(S)″—R_(D)′ or—C(O)-L_(Y)′—N(R_(B))C(O)O-L_(S)″—R_(D)′, wherein L_(Y)′ isC₁-C₆alkylene (e.g., —CH₂—) and optionally substituted with one or moresubstituents selected from R₁, and L_(S)″ preferably is bond. -T-R_(D)′can also be, without limitation, selected from —C(O)-L_(Y)′-L_(S)″—R_(D)′, —C(O)-L_(Y)′—O-L_(S)″—R_(D)′,—C(O)-L_(Y)′—N(R_(B))-L_(S)″—R_(D)′, or—C(O)-L_(Y)′—N(R_(B))S(O)₂-L_(S)″—R_(D)′.

In another embodiment of this aspect, A is

and optionally substituted with one or more R_(A) (e.g., halogen); B is

and is optionally substituted with one or more R_(A) (e.g., halogen);and D is C₅-C₆carbocycle or 5- to 6-membered heterocycle (e.g., phenyl),and is optionally substituted with one or more R_(A), or is substitutedwith J and optionally substituted with one or more R_(A), wherein J isC₃-C₆carbocycle, 3- to 6-membered heterocycle or 6- to 12-memberedbicycle and is optionally substituted with one or more R_(A).Preferably, J is substituted with a C₃-C₆carbocycle or 3- to 6-memberedheterocycle which is independently optionally substituted with one ormore substituents selected from halogen, hydroxy, mercapto, amino,carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano,C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl,C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, C(O)OR_(S) or —N(R_(S)R_(S)′), and Jcan also be optionally substituted with one or more R_(A). Preferably, Dis

wherein R_(M) and R_(N) are as defined above. Also preferably, D is

wherein J and R_(N) are as defined above. When A and/or B arehalo-substituted benzimidazole (e.g., A is

and B is

the compounds of this embodiment can have significantly improvedpharmacokinetic properties as well as improved inhibitory activityagainst certain HCV genotype 1a mutants, as compared to the samecompounds but with unsubstituted benzimidazole. L₁ and L₂ are eachindependently bond or C₁-C₆alkylene, and L₃ is bond, C₁-C₆alkylene or—C(O)—, and L₁, L₂, and L₃ are each independently optionally substitutedwith one or more R_(L). Preferably, L₁, L₂, and L₃ are bond. -T-R_(D)′is independently selected at each occurrence from—C(O)-L_(Y)′—N(R_(B))C(O)-L_(S)″—R_(D)′ or—C(O)-L_(Y)′—N(R_(B))C(O)O-L_(S)″—R_(D)′, wherein L_(Y)′ isC₁-C₆alkylene (e.g., —CH₂—) and optionally substituted with one or moresubstituents selected from R_(L), and L_(S)″ preferably is bond.-T-R_(D)′ can also be, without limitation, selected from—C(O)-L_(Y)′-L_(S)″—R_(D)′, —C(O)-L_(Y)′—O-L_(S)″—R_(D)% —C(O)-L_(Y)′—N(R_(B))-L_(S)″—R_(D)′, or —C(O)-L_(Y)′—N(R_(B))S(O)₂-L_(S)″—R_(D)′. R₂and R₅, taken together with the atoms to which they are attached,preferably form a 5- to 6-membered heterocycle or 6- to 12-memberedbicycle (e.g.,

which is optionally substituted with one or more R_(A). R₉ and R₁₂,taken together with the atoms to which they are attached, preferablyform a 5- to 6-membered heterocycle or 6- to 12-membered bicycle (e.g.,

which is optionally substituted with one or more R_(A). More preferably,R₂ and R₅, taken together with the atoms to which they are attached,form

which is optionally substituted with one or more R_(A); R₉ and R₁₂,taken together with the atoms to which they are attached, form

which is optionally substituted with one or more R_(A).

In still another embodiment of this aspect, A is

and optionally substituted with one or more R_(A) (preferably, A issubstituted with at least one halogen such as F); B is

and is optionally substituted with one or more R_(A) (preferably, B issubstituted with at least one halogen such as F). X is

wherein X₃ is N and is directly linked to -L₃-D, and X is optionallysubstituted with one or more R_(A) or R_(F). D is phenyl, and issubstituted with J and optionally substituted with one or more R_(A). Jis C₃-C₆carbocycle, 3- to 6-membered heterocycle, 6- to 12-memberedbicycle, 10- to 15-membered tricycle or 13- to 15-memberedcarbocycle/heterocycle, and J is optionally substituted with one or moreR_(A). Preferably, J is substituted with a C₃-C₆carbocycle, 3- to6-membered heterocycle, 6- to 12-membered bicycle or 7- to 12-memberedcarbocycle/heterocycle, which is independently optionally substitutedwith one or more substituents selected from (1) halogen, hydroxy,mercapto, amino, carboxy, nitro, oxo; phosphonoxy, phosphono, thioxo,formyl, cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl,C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, —C(O)OR_(S) or —N(R_(S)R_(S)′), or(2) trimethylsilyl, —O—R_(S), —S—R_(S) or —C(O)R_(S); and J can also beoptionally substituted with one or more R_(A). Preferably, D is

wherein J is as defined above, and each R_(N) is independently selectedfrom R_(D) and preferably is hydrogen or halo such as F. L₁ and L₂ areeach independently bond or C₁-C₆alkylene, and L₃ is bond, C₁-C₆alkyleneor —C(O)—, and L₁, L₂, and L₃ are each independently optionallysubstituted with one or more R_(L). Preferably, L₁, L₂, and L₃ are bond.-T-R_(D)′ is independently selected at each occurrence from—C(O)-L_(Y)′—N(R_(B))C(O)-L_(S)″—R_(D)′ or—C(O)-L_(Y)′—N(R_(B))C(O)O-L_(S)″—R_(D)′, wherein L_(Y)′ isC₁-C₆alkylene (e.g., —CH₂—) and optionally substituted with one or moresubstituents selected from R_(L), and L_(S)″ preferably is bond.-T-R_(D)′ can also be, without limitation, selected from—C(O)-L_(Y)′-L_(S)″—R_(D)′, —C(O)-L_(Y)′—O-L_(S)″—R_(D)′,—C(O)-L_(Y)′—N(R_(B))-L_(S)″—R_(D)′, or—C(O)-L_(Y)′-1-N(R_(B))S(O)₂-L_(S)″—R_(D)′. R₂ and R₅, taken togetherwith the atoms to which they are attached, preferably form a 5- to6-membered heterocycle or 6- to 12-membered bicycle (e.g.,

which is optionally substituted with one or more R_(A). R₉ and R₁₂,taken together with the atoms to which they are attached, preferablyform a 5- to 6-membered heterocycle or 6- to 12-membered bicycle (e.g.,

which is optionally substituted with one or more R_(A). More preferably,R₂ and R₅, taken together with the atoms to which they are attached,form

which is optionally substituted with one or more R_(A); R₉ and R₁₂,taken together with the atoms to which they are attached, form

which is optionally substituted with one or more R_(A).

The present invention unexpectedly found that a compound according tothis aspect of the invention (preferably a compound of Formula I_(B) ora pharmaceutically acceptable salt thereof, wherein A is

B is

and A and B are independently optionally substituted with one or moreR_(A) such as one or more halo) showed significantly improved activitiesagainst different HCV genotypes and variants. For instance, when testedagainst HCV replicons of different genotypes in stable cell lines (inthe presence of 5% FBS), and as compared to Example 37 of U.S. PatentApplication Publication No. 2010/0317568, the EC₅₀ values of thecompounds of Examples 3.48, 3.52, 4.38, and 5.1 were at least about6-fold less than that of Example 37 against genotype 1a, at least about3-fold less against genotype 3a, at least about 50-fold less againstgenotype 6a, and significantly less against genotype 2a. In addition,when tested against HCV genotype 1a replicons containing certain NS5Amutations in transient transfection assays, and as compared to Example37 of U.S. Patent Application Publication No. 2010/0317568, the EC₅₀values of the compounds of Examples 3.48, 3.52, 4.38, and 5.1 were atleast about 130-fold less than that of Example 37 against the L31Vvariant, at least about 7,500 fold less against the M28T variant, atleast about 80-fold less against the M28V variant, at least about500-fold less against the Q30E variant, at least about 300-fold lessagainst the Q30R variant, at least about 800-fold less against the Y93Cvariant, at least about 1,500-fold less against the Y93H variant, andsignificantly less against the Q30H variant. Likewise, when testedagainst HCV genotype 1b replicons containing certain NS5A mutations intransient transfection assays, and as compared to Example 37 of U.S.Patent Application Publication No. 2010/0317568, the EC₅₀ value of thecompound of Example 5.1 was at least about 10-fold less than that ofExample 37 against the Y93H variant.

Accordingly, the present invention features methods of treatingdifferent HCV genotype or variant infection. The methods compriseadministering a compound of Formula I_(B), or a pharmaceuticallyacceptable salt thereof, to a patient infected with HCV genotype 1a, 1b,2a, 2b, 3a, 4a, 5a or 6a, or infected with one of the variants describedabove. Preferably, A is

B is

and A and B are independently optionally substituted with one or moreR_(A) such as one or more halo. Other compounds described in this aspectof the invention or any embodiment thereunder, as well as the titlecompounds in the Examples described below, may also be used. In oneembodiment, the patient being treated is infected with HCV genotype 1,such as 1a. In another embodiment, the patient being treated is infectedwith HCV genotype 2, such as 2a. In still another embodiment, thepatient being treated is infected with HCV genotype 3, such as 3a. Inanother embodiment, the patient being treated is infected with HCVgenotype 4, such as 4a. In a further embodiment, the patient beingtreated is infected with HCV genotype 5, such as 5a. In yet anotherembodiment, the patient being treated is infected with HCV genotype 6,such as 6a.

In yet another aspect, the present invention further features compoundsof Formula I_(C) and pharmaceutically acceptable salts thereof.

wherein:

-   -   R_(NB) is R_(B);    -   R_(C)′ is each independently selected from R_(C);    -   R_(D)′ is each independently selected from R_(D);    -   R₂ and R₅, taken together with the atoms to which they are        attached, form a 3- to 12-membered heterocycle which is        optionally substituted with one or more R_(A);    -   R₉ and R₁₂, taken together with the atoms to which they are        attached, form a 3- to 12-membered heterocycle which is        optionally substituted with one or more R_(A);    -   A, B, D, X, L₁, L₂, L₃, T, R_(A), R_(B), R_(C), and R_(D) are as        described above in Formula I.

In this aspect, A preferably is C₅-C₆carbocycle or 5- to 6-memberedheterocycle, and is optionally substituted with one or more R_(A); and Bpreferably is 8- to 12-membered bicycle (such as

and is optionally substituted with one or more R_(A). Z₁ is O, S, NH orCH₂; Z₂ is N or CH; Z₃ is N or CH; Z₄ is O, S, NH or CH₂; and W₁, W₂,W₃, W₄, W₅ and W₆ are each independently selected from CH or N.

More preferably, A is phenyl

and is optionally substituted with one or more R_(A); and B is

and is optionally substituted with one or more R_(A), where Z₁, Z₂, Z₃,Z₄, W₁, W₂, W₃, W₄, W₅, W₆ are as defined above. Preferably, Z₃ is N andZ₄ is NH. For instance, B can be

(e.g.,

(e.g.,

and is optionally substituted with one or more R_(A).

Also preferably, A is C₅-C₆carbocycle (e.g., phenyl such as

or 5- to 6-membered heterocycle; and B is

(e.g.,

wherein B′ is selected from C₅-C₆carbocycle or 5- to 6-memberedheterocycle. A and B are independently optionally substituted with oneor more R_(A).

D preferably is selected from C₅-C₆carbocycle, 5- to 6-memberedheterocycle, or 6- to 12-membered bicycles, and is optionallysubstituted with one or more R_(A). D can also be preferably selectedfrom C₁-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl, and is optionallysubstituted with one or more substituents selected from R_(L). Morepreferably, D is C₅-C₆carbocycle, 5- to 6-membered heterocycle, or 6- to12-membered bicycles, and is substituted with one or more R_(M), whereR_(M) is halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, or-L_(S)-R_(E). Also preferably, D is phenyl, and is optionallysubstituted with one or more R_(A). More preferably, D is phenyl, and issubstituted with one or more R_(M), wherein R_(M) is as defined above.Highly preferably, D is

wherein R_(M) is as defined above, and each R_(N) is independentlyselected from R_(D) and preferably is hydrogen. One or more R_(N) canalso preferably be halo such as F.

D is also preferably pyridinyl, pyrimidinyl, or thiazolyl, optionallysubstituted with one or more R_(A). More preferably D is pyridinyl,pyrimidinyl, or thiazolyl, and is substituted with one or more R_(M).Highly preferably, D is

wherein R_(M) is as defined above, and each R_(N) is independentlyselected from R_(D) and preferably is hydrogen. One or more R_(N) canalso preferably be halo such as F. D is also preferably indanyl,4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, or indazolyl,and is optionally substituted with one or more R_(A). More preferably Dis indanyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl,indazolyl, or benzo[d][1,3]dioxol-5-yl, and is substituted with one ormore R_(M). Highly preferably, D is

and is optionally substituted with one or more R_(M).

Preferably, R_(M) is halogen, hydroxy, mercapto, amino, carboxy, nitro,oxo, phosphonoxy, phosphono, thioxo, cyano; or C₁-C₆alkyl, C₂-C₆alkenylor C₂-C₆alkynyl, each of which is independently optionally substitutedat each occurrence with one or more substituents selected from halogen,hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,thioxo, formyl or cyano; or C₃-C₆carbocycle or 3- to 6-memberedheterocycle, each of which is independently optionally substituted ateach occurrence with one or more substituents selected from halogen,hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,thioxo, formyl, cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆haloalkyl, C₂-C₆haloalkenyl or C₂-C₆haloalkynyl. More preferably,R_(M) is halogen, hydroxy, mercapto, amino, carboxy; or C₁-C₆alkyl,C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is independently optionallysubstituted at each occurrence with one or more substituents selectedfrom halogen, hydroxy, mercapto, amino or carboxy. Highly preferably,R_(M) is C₁-C₆alkyl which is optionally substituted with one or moresubstituents selected from halogen, hydroxy, mercapto, amino or carboxy.

Also preferably, R_(M) is halogen, hydroxy, mercapto, amino, carboxy,nitro, oxo, phosphonoxy, phosphono, thioxo, or cyano; or R_(M) is-L_(S)-R_(E), wherein L_(S) is a bond or C₁-C₆alkylene, and R_(E) is—N(R_(S)R_(S)′), —O—R_(S), —C(O)R_(S), —C(O)OR_(S), —C(O)N(R_(S)R_(S)′),—N(R_(S))C(O)R_(S)′, —N(R_(S))C(O)OR_(S)′, —N(R_(S))SO₂R_(S)′,—SO₂R_(S), —SR_(S), or —P(O)(OR_(S))₂, wherein R_(S) and R_(S)′ can be,for example, each independently selected at each occurrence from (1)hydrogen or (2) C₁-C₆alkyl optionally substituted at each occurrencewith one or more halogen, hydroxy, —O—C₁-C₆alkyl or 3- to 6-memberedheterocycle; or R_(M) is C₁-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl, eachof which is independently optionally substituted at each occurrence withone or more substituents selected from halogen, hydroxy, mercapto,amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl orcyano; or R_(M) is C₃-C₆carbocycle or 3- to 6-membered heterocycle, eachof which is independently optionally substituted at each occurrence withone or more substituents selected from halogen, hydroxy, mercapto,amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl,cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl,C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, —C(O)OR_(S), or —N(R_(S)R_(S)′).More preferably, R_(M) is halogen (e.g., fluoro, chloro, bromo, iodo),hydroxy, mercapto, amino, carboxy, or C₁-C₆alkyl (e.g., methyl,isopropyl, tert-butyl), C₂-C₆alkenyl or C₂-C₆alkynyl, each of which isindependently optionally substituted at each occurrence with one or moresubstituents selected from halogen, hydroxy, mercapto, amino, cyano, orcarboxy. For example R_(M) is CF₃, —C(CF₃)₂—OH, —C(CH₃)₂—CN,—C(CH₃)₂—CH₂OH, or —C(CH₃)₂—CH₂NH₂. Also preferably R_(M) is-L_(S)—R_(E) where L_(S) is a bond and R_(E) is —N(R_(S)R_(S)′),—O—R_(S), —N(R_(S))C(O)OR_(S)′, —N(R_(S))SO₂R_(S)′, —SO₂R_(S), or—SR_(S). For example where L_(S) is a bond, R_(E) is —N(C₁-C₆alkyl)₂(e.g., —NMe₂); C₆alkyl)₂ (e.g. —N(CH₂CH₂OMe)₂);—N(C₁-C₆alkyl)(C₁-C₆alkylene—O—C₁-C₆alkyl) (e.g. —N(CH₃)(CH₂CH₂OMe));—O—C₁-C₆alkyl (e.g., —O-Me, —O-Et, —O-isopropyl, —O-tert-butyl,—O-n-hexyl); —O—C₁-C₆haloalkyl (e.g., —OCF₃, —OCH₂CF₃);—O—C₁-C₆alkylene-piperidine (e.g., —O—CH₂CH₂-1-piperidyl);—N(C₁-C₆alkyl)C(O)OC₁-C₆alkyl (e.g., —N(CH₃)C(O)O—CH₂CH(CH₃)₂),—N(C₁-C₆alkyl)SO₂C₁-C₆alkyl (e.g., —N(CH₃)SO₂CH₃); —SO₂C₁-C₆alkyl (e.g.,—SO₂Me); —SO₂C₁-C₆haloalkyl (e.g., —SO₂CF₃); or —S—C₁-C₆haloalkyl (e.g.,SCF₃). Also preferably R_(M) is -L_(S)-R_(E) where L_(S) isC₁-C₆alkylene (e.g., —CH₂—, —C(CH₃)₂—, —C(CH₃)₂—CH₂—) and R_(E) is—O—R_(S), —C(O)OR_(S), —N(R_(S))C(O)OR_(S)′, or —P(O)(OR_(S))₂. Forexample R_(M) is —C₁-C₆alkylene—O—R_(S) (e.g., —C(CH₃)₂—CH₂—OMe);—C₁-C₆alkylene—C(O)OR_(S) (e.g., —C(CH₃)₂—C(O)OMe);—C₁-C₆alkylene—N(R_(S))C(O)OR_(S)′ (e.g., —C(CH₃)₂—CH₂—NHC(O)OCH₃); or—C₁-C₆alkylene-P(O)(OR_(S))₂ (e.g., —CH₂—P(O)(OEt)₂). Also morepreferably R_(M) is C₃-C₆carbocycle or 3- to 6-membered heterocycle,each of which is independently optionally substituted at each occurrencewith one or more substituents selected from halogen, hydroxy, mercapto,amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl,cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl,C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, —C(O)OR_(S), or —N(R_(S)R_(S)′). Forexample R_(M) is cycloalkyl (e.g., cyclopropyl,2,2-dichloro-1-methylcycloprop-1-yl, cyclohexyl), phenyl, heterocyclyl(e.g., morpholin-4-yl, 1,1-dioxidothiomorpholin-4-yl,4-methylpiperazin-1-yl, 4-methoxycarbonylpiperazin-1-yl,pyrrolidin-1-yl, piperidin-1-yl, 4-methylpiperidin-1-yl,3,5-dimethylpiperidin-1-yl, 4,4-difluoropiperidin-1-yl,tetrahydropyran-4-yl, pyridinyl, pyridin-3-yl,6-(dimethylamino)pyridin-3-yl). Highly preferably, R_(M) is C₁-C₆alkylwhich is optionally substituted with one or more substituents selectedfrom halogen, hydroxy, mercapto, amino or carboxy (e.g., tert-butyl,CF₃).

More preferably, D is C₅-C₆carbocycle, 5- to 6-membered heterocycle or6- to 12-membered bicycle and is substituted with J and optionallysubstituted with one or more R_(A), wherein J is C₃-C₆carbocycle, 3- to6-membered heterocycle or 6- to 12-membered bicycle and is optionallysubstituted with one or more R_(A). Preferably, J is substituted with aC₃-C₆carbocycle or 3- to 6-membered heterocycle, wherein saidC₃-C₆carbocycle or 3- to 6-membered heterocycle is independentlyoptionally substituted with one or more substituents selected fromhalogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy,phosphono, thioxo, formyl, cyano, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₁-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl,C(O)OR_(S) or —N(R_(S)R_(S)′), and J can also be optionally substitutedwith one or more R_(A). Also preferably, D is C₅-C₆carbocycle or 5- to6-membered heterocycle and is substituted with J and optionallysubstituted with one or more R_(A), and J is C₃-C₆carbocycle or 3- to6-membered heterocycle and is optionally substituted with one or moreR_(A), and preferably, J is at least substituted with a C₃-C₆carbocycleor 3- to 6-membered heterocycle which is independently optionallysubstituted with one or more substituents selected from halogen,hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,thioxo, formyl, cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, C(O)OR_(S) or—N(R_(S)R_(S)′). Also preferably, D is C₅-C₆carbocycle or 5- to6-membered heterocycle and is substituted with J and optionallysubstituted with one or more R_(A), and J is 6- to 12-membered bicycle(e.g., a 7- to 12-membered fused, bridged or spiro bicycle comprising anitrogen ring atom through which J is covalently attached to D) and isoptionally substituted with one or more R_(A). More preferably, D isphenyl and is substituted with J and optionally substituted with one ormore R_(A), and J is C₃-C₆carbocycle, 3- to 6-membered heterocycle or 6-to 12-membered bicycle and is optionally substituted with one or moreR_(A), and preferably J is at least substituted with a C₃-C₆carbocycleor 3- to 6-membered heterocycle which is independently optionallysubstituted with one or more substituents selected from halogen,hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,thioxo, formyl, cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, C(O)OR_(S) or—N(R_(S)R_(S)′). Highly preferably, D is

wherein each R_(N) is independently selected from R_(D) and preferablyis hydrogen or halogen, and J is C₃-C₆carbocycle, 3- to 6-memberedheterocycle or 6- to 12-membered bicycle and is optionally substitutedwith one or more R_(A), and preferably J is at least substituted with aC₃-C₆carbocycle or 3- to 6-membered heterocycle which is independentlyoptionally substituted with one or more substituents selected fromhalogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy,phosphono, thioxo, formyl, cyano, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₁-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl,C(O)OR_(S) or —N(R_(S)R_(S)′). Also preferably, D is

wherein each R_(N) is independently selected from R_(D) and preferablyis hydrogen or halogen, and J is C₃-C₆carbocycle or 3- to 6-memberedheterocycle and is substituted with a C₃-C₆carbocycle or 3- to6-membered heterocycle which is independently optionally substitutedwith one or more substituents selected from halogen, hydroxy, mercapto,amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl,cyano, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl, C₂-C₆haloalkenyl,C₂-C₆haloalkynyl, C(O)OR_(S) or —N(R_(S)R_(S)′), and J can also beoptionally substituted with one or more R_(A). Also preferably, D is

and J is C₃-C₆carbocycle or 3- to 6-membered heterocycle and isoptionally substituted with one or more R_(A), and preferably J is atleast substituted with a C₃-C₆carbocycle or 3- to 6-membered heterocyclewhich is independently optionally substituted with one or moresubstituents selected from halogen, hydroxy, mercapto, amino, carboxy,nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl, C₂-C₆haloalkenyl,C₂-C₆haloalkynyl, C(O)OR_(S) or —N(R_(S)R_(S)′).

X preferably is C₅-C₆carbocycle, 5- to 6-membered heterocycle, or 6- to12-membered bicycles (e.g.,

wherein X₃ is N and is directly linked to -L₃-D), and is optionallysubstituted with one or more R_(A) or R_(F). Non-limiting examples of Xare described hereinabove.

L₁ and L₂ are preferably independently bond or C₁-C₆alkylene, L₃ ispreferably selected from bond, C₁-C₆alkylene or —C(O)—, and L₁, L₂, andL₃ are each independently optionally substituted with one or more R_(L).More preferably, L₁, L₂ and L₃ are each independently bond orC₁-C₆alkylene (e.g., —CH₂— or —CH₂CH₂—), and are each independentlyoptionally substituted with one or more R_(L). Highly preferably, L₁, L₂and L₃ are bond. L₁ and L₂ can be the same or different.

R₂ and R₅, taken together with the atoms to which they are attached,preferably form a 5- to 6-membered heterocycle or 6- to 12-memberedbicycle (e.g.,

which is optionally substituted with one or more R_(A). R₉ and R₁₂,taken together with the atoms to which they are attached, preferablyform a 5- to 6-membered heterocycle or 6- to 12-membered bicycle (e.g.,

which is optionally substituted with one or more R_(A).

-T-R_(D)′ can be, without limitation, independently selected at eachoccurrence from —C(O)-L_(Y)′—R_(D)′, —C(O)O-L_(Y)′—R_(D)′,—C(O)-L_(Y)′—N(R_(B))C(O)O-L_(S)-C(O)-L_(Y)′—N(R_(B))C(O)O-L_(S)″R_(D)′,—N(R_(B))C(O)-L_(Y)′—N(R_(B))C(O)-L_(S)″—R_(D)′,—N(R_(B))C(O)-L_(Y)′—N(R_(B))C(O)O-L_(S)″—R_(D)′, or—N(R_(B))C(O)-L_(Y)′—N(R_(B))-L_(S)″—R_(D)′, wherein L_(Y)′ is eachindependently L_(S)′ and, preferably, is each independentlyC₁-C₆alkylene (e.g., —CH₂— or

and optionally substituted with one or more substituents selected fromR_(L). Preferably, -T-R_(D)′ is independently selected at eachoccurrence from —C(O)-L_(Y)′-M′-L_(S)″—R_(D)′ or—N(R_(B))C(O)-L_(Y)′-M′-L_(S)″—R_(D)′. More preferably, -T-R_(D)′ isindependently selected at each occurrence from—C(O)-L_(Y)′—N(R_(B))C(O)-L_(S)″—R_(D)′ or—C(O)-L_(Y)′—N(R_(B))C(O)O-L_(S)″—R_(D)′. Highly preferably, -T-R_(D)′is independently selected at each occurrence from—C(O)-L_(Y)′—N(R_(B))C(O)—R_(D)′ or —C(O)-L_(Y)′—N(R_(B))C(O)O—R_(D)′,wherein L_(Y)′ preferably is each independently C₁-C₆alkylene (e.g.,—CH₂— or

and optionally substituted with one or more substituents selected fromR_(L).

R_(NB) and R_(C)′ are preferably hydrogen, and R_(D)′ preferably isindependently selected at each occurrence from R_(E). More preferably,R_(D)′ is independently selected at each occurrence from C₁-C₆alkyl,C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is independently optionallysubstituted at each occurrence with one or more substituents selectedfrom halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,phosphonoxy, phosphono, thioxo, formyl, cyano, C₃-C₆carbocycle or 3- to6-membered heterocycle; or C₃-C₆carbocycle or 3- to 6-memberedheterocycle, each of which is independently optionally substituted ateach occurrence with one or more substituents selected from halogen,hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,thioxo, formyl, cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆haloalkyl, C₂-C₆haloalkenyl or C₂-C₆haloalkynyl.

R_(A) preferably is halogen, hydroxy, mercapto, amino, carboxy, nitro,oxo, phosphonoxy, phosphono, thioxo, cyano; or C₂-C₆alkenyl orC₂-C₆alkynyl, each of which is independently optionally substituted ateach occurrence with one or more substituents selected from halogen,hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,thioxo, formyl or cyano; or C₃-C₆carbocycle or 3- to 6-memberedheterocycle, each of which is independently optionally substituted ateach occurrence with one or more substituents selected from halogen,hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,thioxo, formyl, cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆haloalkyl, C₂-C₆haloalkenyl or C₂-C₆haloalkynyl; or -L_(A)-O—R_(S),-L_(A)-S—R_(S), -L_(A)-C(O)R_(S), -L_(A)-OC(O)R_(S), -L_(A)-C(O)OR_(S),-L_(A)-N(R_(S)R_(S)′), -L_(A)-S(O)R_(S), -L_(A)-SO₂R_(S),-L_(A)-C(O)N(R_(S)R_(S)′), -L_(A)-N(R_(S))C(O)R_(S)′.-L_(A)-N(R_(S))C(O)N(R_(S)′R_(S)″), -L_(A)-N(R_(S))SO₂R_(S)′,-L_(A)-SO₂N(R_(S)R_(S)′), -L_(A)-N(R_(S))SO₂N(R_(S)′R_(S)″),-L_(A)-N(R_(S))S(O)N(R_(S)′R_(S)″), -L_(A)-OS(O)—R_(S),-L_(A)-OS(O)₂—R_(S), -L_(A)-S(O)₂OR_(S), -L_(A)-S(O)OR_(S),-L_(A)-OC(O)OR_(S), -L_(A)-N(R_(S))C(O)OR_(S)′,-L_(A)-OC(O)N(R_(S)R_(S)′), -L_(A)-N(R_(S))S(O)—R_(S)′,-L_(A)-S(O)N(R_(S)R_(S)′) or -L_(A)-C(O)N(R_(S))C(O)—R_(S)′, whereinL_(A) is bond, C₁-C₆alkylene, C₂-C₆alkenylene or C₂-C₆alkynylene.

More preferably, R_(A) is halogen, hydroxy, mercapto, amino, carboxy,nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or C₁-C₆alkyl,C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is independently optionallysubstituted at each occurrence with one or more substituents selectedfrom halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,phosphonoxy, phosphono, thioxo, formyl or cyano; or C₃-C₆carbocycle or3- to 6-membered heterocycle, each of which is independently optionallysubstituted at each occurrence with one or more substituents selectedfrom halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,phosphonoxy, phosphono, thioxo, formyl, cyano, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₁-C₆haloalkyl, C₂-C₆haloalkenyl or C₂-C₆haloalkynyl.

Highly preferably, R_(A) is halogen, hydroxy, mercapto, amino, carboxy,nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or C₁-C₆alkyl,C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is independently optionallysubstituted at each occurrence with one or more substituents selectedfrom halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,phosphonoxy, phosphono, thioxo, formyl or cyano.

L_(S), L_(S)′ and L_(S)″ preferably are each independently selected ateach occurrence from bond; or C₁-C₆alkylene, C₂-C₆alkenylene orC₂-C₆alkynylene.

In one embodiment of this aspect, A is phenyl, and is optionallysubstituted with one or more R_(A); and B is

and is optionally substituted with one or more R_(A), wherein Z₁ is O,S, NH or CH₂; and Z₂ is N or CH. D is C₅-C₆carbocycle or 5- to6-membered heterocycle (e.g., phenyl), and is optionally substitutedwith one or more R_(A), or is substituted with J and optionallysubstituted with one or more R_(A), wherein J is C₃-C₆carbocycle, 3- to6-membered heterocycle or 6- to 12-membered bicycle and is optionallysubstituted with one or more R_(A). Preferably, J is substituted with aC₃-C₆carbocycle or 3- to 6-membered heterocycle which is independentlyoptionally substituted with one or more substituents selected fromhalogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy,phosphono, thioxo, formyl, cyano, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₁-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl,C(O)OR_(S) or —N(R_(S)R_(S)′), and J can also be optionally substitutedwith one or more R_(A). Preferably, D is

wherein R_(M) and R_(N) are as defined above. Also preferably, D is

wherein J and R_(N) are as defined above. L₁ and L₂ are eachindependently bond or C₁-C₆alkylene, and L₃ is bond, C₁-C₆alkylene or—C(O)═, and L₁, L₂, and L₃ are each independently optionally substitutedwith one or more R_(L): Preferably, L₁, L₂, and L₃ are bond. -T-R_(D)′is independently selected at each occurrence from—C(O)-L_(Y)′—N(R_(B))C(O)-L_(S)″—R_(D)′ or—C(O)-L_(Y)′—N(R_(B))C(O)O-L_(S)″—R_(D)′, wherein L_(Y)′ isC₁-C₆alkylene (e.g., —CH₂—) and optionally substituted with one or moresubstituents selected from R_(L), and L_(S)″ preferably is bond.-T-R_(D)′ can also, be, without limitation, selected from—C(O)-L_(Y)′-L_(S)″—R_(D)′, —C(O)-L_(Y)′—O-L_(S)″—R_(D)′,—C(O)-L_(Y)′—N(R_(B))— L_(S)″—R_(D)′, or—C(O)-L_(Y)′—N(R_(B))S(O)₂-L_(S)″—R_(D)′. Preferably, R₂ and R₅, takentogether with the atoms to which they are attached, form

which is optionally substituted with one or more R_(A); R₉ and R₁₂,taken together with the atoms to which they are attached, form

which is optionally substituted with one or more R_(A).

In another embodiment of this aspect, A is phenyl

and is optionally substituted with one or more R_(A) (preferably, A issubstituted with at least one halogen such as F); and B is

and is optionally substituted with one or more R_(A) (preferably, B issubstituted with at least one halogen such as F). X is

wherein X₃ is N and is directly linked to -L₃-D, and X is optionallysubstituted with one or more R_(A) or R_(F). D is phenyl, and issubstituted with J and optionally substituted with one or more R_(A). Jis C₃-C₆carbocycle, 3- to 6-membered heterocycle, 6- to 12-memberedbicycle, 10- to 15-membered tricycle or 13- to 15-memberedcarbocycle/heterocycle, and J is optionally substituted with one or moreR_(A). Preferably, J is substituted with a C₃-C₆carbocycle, 3- to6-membered heterocycle, 6- to 12-membered bicycle or 7 to 12-memberedcarbocycle/heterocycle, which is independently optionally substitutedwith one or more substituents selected from (1) halogen, hydroxy,mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo,formyl, cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl,C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, —C(O)OR_(S) or —N(R_(S)R_(S)′), or(2) trimethylsilyl, —O—R_(S), —S—R_(S) or —C(O)R_(S); and J can also beoptionally substituted with one or more R_(A). Preferably, D is

wherein J is as defined above, and each R_(N) is independently selectedfrom R_(D) and preferably is hydrogen or halo such as F. L₁ and L₂ areeach independently bond or C₁-C₆alkylene, and L₃ is bond, C₁-C₆alkyleneor —C(O)—, and L₁, L₂, and L₃ are each independently optionallysubstituted with one or more R_(L). Preferably, L₁, L₂, and L₃ are bond.-T-R_(D)′ is independently selected at each occurrence from—C(O)-L_(Y)′—N(R_(B))C(O)-L_(S)″—R_(D)′ or —C(O)-L_(Y)′—N(R_(B))C(O)O-L_(S)″—R_(D)′, wherein L_(Y)′ is C₁-C₆alkylene (e.g.,—CH₂—) and optionally substituted with one or more substituents selectedfrom R_(L), and L_(S)″ preferably is bond. -T-R_(D)′ can also be,without limitation, selected from —C(O)-L_(Y)′-L_(S)″—R_(D)′,—C(O)-L_(Y)′—N(R_(B))-L_(S)′-R_(D)′, or—C(O)-L_(Y)′—N(R_(B))S(O)₂-L_(S)″—R_(D)′. Preferably, R₂ and R₅, takentogether with the atoms to which they are attached, form a 5- to6-membered heterocyclic ring (e.g.,

or 6- to 12-membered bicycle (e.g.,

which is optionally substituted with one or more R_(A); R₉ and R₁₂,taken together with the atoms to which they are attached, form a 5- to6-membered heterocyclic ring (e.g.,

or 6- to 12-membered bicycle (e.g.,

which is optionally substituted with one or more R_(A).

In yet another aspect, the present invention features compounds ofFormula I_(D) and pharmaceutically acceptable salts thereof.

wherein:

-   -   G₁ and G₂ are each independently selected from C₅-C₆carbocycle        or 5- to 6-membered heterocycle, and are each independently        optionally substituted with one or more R_(A);    -   R_(C)′ is each independently selected from R_(C);    -   R_(D)′ is each independently selected from R_(D);    -   R₂ and R₅, taken together with the atoms to which they are        attached, form a 3- to 12-membered heterocycle which is        optionally substituted with one or more R_(A);    -   R₉ and R₁₂, taken together with the atoms to which they are        attached, form a 3- to 12-membered heterocycle which is        optionally substituted with one or more R_(A);    -   A, B, D, X, L₁, L₂, L₃, T, R_(A), R_(C), and R_(D) are as        described above in Formula I.

In this aspect, A and B preferably are independently selected fromC₅-C₆carbocycle or 5- to 6-membered heterocycle, and are eachindependently optionally substituted with one or more R_(A). Morepreferably, at least one of A and B is phenyl

and is optionally substituted with one or more R_(A). Highly preferably,both A and B are each independently phenyl

and are each independently optionally substituted with one or moreR_(A).

D preferably is selected from C₅-C₆carbocycle, 5- to 6-memberedheterocycle, or 8- to 12-membered bicycles, and is optionallysubstituted with one or more R_(A). D can also be preferably selectedfrom C₁-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl, and is optionallysubstituted with one or more R_(L). More preferably, D isC₅-C₆carbocycle, 5- to 6-membered heterocycle, or 6- to 12-memberedbicycles, and is substituted with one or more R_(M), where R_(M) ishalogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, or-L_(S)-R_(E). Also preferably, D is phenyl, and is optionallysubstituted with one or more R_(A). More preferably, D is phenyl, and issubstituted with one or more R_(M), wherein R_(M) is as defined above.Highly preferably, D is

wherein R_(M) is as defined above, and each R_(N) is independentlyselected from R_(D) and preferably is hydrogen. One or more R_(N) canalso preferably be halo such as F.

D is also preferably pyridinyl, pyrimidinyl, or thiazolyl, optionallysubstituted with one or more R_(A). More preferably D is pyridinyl,pyrimidinyl, or thiazolyl, and is substituted with one or more R_(M).Highly preferably, D is

wherein R_(M) is as defined above, and each R_(N) is independentlyselected from R_(D) and preferably is hydrogen. One or more R_(N) canalso preferably be halo such as F. D is also preferably indanyl,4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, or indazolyl,and is optionally substituted with one or more R_(A). More preferably Dis indanyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl,indazolyl, or benzo[d][1,3]dioxol-5-yl, and is substituted with one ormore R_(M). Highly preferably, D is

and is optionally substituted with one or more R_(M).

Preferably, R_(M) is halogen, hydroxy, mercapto, amino, carboxy, nitro,oxo, phosphonoxy, phosphono, thioxo, cyano; or C₁-C₆alkyl, C₂-C₆alkenylor C₂-C₆alkynyl, each of which is independently optionally substitutedat each occurrence with one or more substituents selected from halogen,hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,thioxo, formyl or cyano; or C₃-C₆carbocycle or 3- to 6-memberedheterocycle, each of which is independently optionally substituted ateach occurrence with one or more substituents selected from halogen,hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,thioxo, formyl, cyano, C₁-C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl,C₂-C₆haloalkenyl or C₂-C₆haloalkynyl. More preferably, R_(M) is halogen,hydroxy, mercapto, amino, carboxy; or C₁-C₆alkyl, C₂-C₆alkenyl orC₂-C₆alkynyl, each of which is independently optionally substituted ateach occurrence with one or more substituents selected from halogen,hydroxy, mercapto, amino or carboxy. Highly preferably, R_(M) isC₁-C₆alkyl which is optionally substituted with one or more substituentsselected from halogen, hydroxy, mercapto, amino or carboxy.

Also preferably, R_(M) is halogen, hydroxy, mercapto, amino, carboxy,nitro, oxo, phosphonoxy, phosphono, thioxo, or cyano; or R_(M) is-L_(S)-R_(E), wherein L_(S) is a bond or C₁-C₆alkylene, and R_(E) is—N(R_(S)R_(S)′), —O—R_(S), —C(O)R_(S), —C(O)OR_(S), —C(O)N(R_(S)R_(S)′),—N(R_(S))C(O)R_(S)′, —N(R_(S))C(O)OR_(S)′, —N(R_(S))SO₂R_(S)′,—SO₂R_(S), —SR_(S), or —P(O)(OR_(S))₂, wherein R_(S) and R_(S)′ can be,for example, each independently selected at each occurrence from (1)hydrogen or (2) C₁-C₆alkyl optionally substituted at each occurrencewith one or more halogen, hydroxy, —O—C₁-C₆alkyl or 3- to 6-memberedheterocycle; or R_(M) is C₁-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl, eachof which is independently optionally substituted at each occurrence withone or more substituents selected from halogen, hydroxy, mercapto,amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl orcyano; or R_(M) is C₃-C₆carbocycle or 3- to 6-membered heterocycle, eachof which is independently optionally substituted at each occurrence withone or more substituents selected from halogen, hydroxy, mercapto,amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl,cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl,C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, —C(O)OR_(S), or —N(R_(S)R_(S)′).More preferably, R_(M) is halogen (e.g., fluoro, chloro, bromo, iodo),hydroxy, mercapto, amino, carboxy, or C₁-C₆alkyl (e.g., methyl,isopropyl, tert-butyl), C₂-C₆alkenyl or C₂-C₆alkynyl, each of which isindependently optionally substituted at each occurrence with one or moresubstituents selected from halogen, hydroxy, mercapto, amino, cyano, orcarboxy. For example R_(M) is CF₃, —C(CF₃)₂—OH, —C(CH₃)₂—CN,—C(CH₃)₂—CH₂OH, or —C(CH₃)₂—CH₂NH₂. Also preferably R_(M) is-L_(S)-R_(E) where L_(S) is a bond and R_(E) is —N(R_(S)R_(S′)),—O—R_(S), —N(R_(S))C(O)OR_(S)′, —N(R_(S))SO₂R_(S)′, —SO₂R_(S), or—SR_(S). For example where L_(S) is a bond, R_(E) is —N(C₁-C₆alkyl)₂(e.g., —NMe₂); —N(C₁-C₆alkylene—O—C₁-C₆alkyl)₂ (e.g. —N(CH₂CH₂OMe)₂);—N(C₁-C₆alkyl)(C₁-C₆alkylene—O—C₁-C₆alkyl) (e.g. —N(CH₃)(CH₂CH₂OMe));—O—C₁-C₆alkyl (e.g., —O-Me, —O-Et, —O-isopropyl, —O-tert-butyl,—O-n-hexyl); —O—C₁-C₆haloalkyl (e.g., —OCF₃, —OCH₂CF₃);—O—C₁-C₆alkylene-piperidine (e.g., —O —CH₂CH₂-1-piperidyl);—N(C₁-C₆alkyl)C(O)OC₁-C₆alkyl (e.g., —N(CH₃)C(O)O—CH₂CH(CH₃)₂),—N(C₁-C₆alkyl)SO₂C₁-C₆alkyl (e.g., —N(CH₃)SO₂CH₃); —SO₂C₁-C₆alkyl (e.g.,—SO₂Me); —SO₂C₁-C₆haloalkyl (e.g., —SO₂CF₃); or —S—C₁-C₆haloalkyl (e.g.,SCF₃). Also preferably R_(M) is -L_(S)-R_(E) where L_(S) isC₁-C₆alkylene (e.g., —CH₂—, —C(CH₃)₂—, —C(CH₃)₂—CH₂—) and R_(E) is—O—R_(S), —C(O)OR_(S), —N(R_(S))C(O)OR_(S)′, or —P(O)(OR_(S))₂. Forexample R_(M) is —C₁-C₆alkylene—O—R_(S) (e.g., —C(CH₃)₂—CH₂—OMe);—C₁-C₆alkylene—C(O)OR_(S) (e.g., —C(CH₃)₂—C(O)OMe);—C₁-C₆alkylene—N(R_(S))C(O)OR_(S)′ (e.g., —C(CH₃)₂—CH₂—NHC(O)OCH₃); or—C₁-C₆alkylene-P(O)(OR_(S))₂ (e.g., —CH₂—P(O)(OEt)₂). Also morepreferably R_(M) is C₃-C₆carbocycle or 3- to 6-membered heterocycle,each of which is independently optionally substituted at each occurrencewith one or more substituents selected from halogen, hydroxy, mercapto,amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl,cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl,C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, —C(O)OR_(S), or —N(R_(S)R_(S)′). Forexample R_(M) is cycloalkyl (e.g., cyclopropyl,2,2-dichloro-1-methylcycloprop-1-yl, cyclohexyl), phenyl, heterocyclyl(e.g., morpholin-4-yl, 1,1-dioxidothiomorpholin-4-yl,4-methylpiperazin-1-yl, 4-methoxycarbonylpiperazin-1-yl,pyrrolidin-1-yl, piperidin-1-yl, 4-methylpiperidin-1-yl,3,5-dimethylpiperidin-1-yl, 4,4-difluoropiperidin-1-yl,tetrahydropyran-4-yl, pyridinyl, pyridin-3-yl,6-(dimethylamino)pyridin-3-yl). Highly preferably, R_(M) is C₁-C₆alkylwhich is optionally substituted with one or more substituents selectedfrom halogen, hydroxy, mercapto, amino or carboxy (e.g., tert-butyl,CF₃).

More preferably, D is C₅-C₆carbocycle, 5- to 6-membered heterocycle or6- to 12-membered bicycle and is substituted with J and optionallysubstituted with one or more R_(A), wherein J is C₃-C₆carbocycle, 3- to6-membered heterocycle or 6- to 12-membered bicycle and is optionallysubstituted with one or more R_(A). Preferably, J is substituted with aC₃-C₆carbocycle or 3- to 6-membered heterocycle, wherein saidC₃-C₆carbocycle or 3- to 6-membered heterocycle is independentlyoptionally substituted with one or more substituents selected fromhalogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy,phosphono, thioxo, formyl, cyano, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₁-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl,C(O)OR_(S) or —N(R_(S)R_(S)′), and J can also be optionally substitutedwith one or more R_(A). Also preferably, D is C₅-C₆carbocycle or 5- to6-membered heterocycle and is substituted with J and optionallysubstituted with one or more R_(A), and J is C₃-C₆carbocycle or 3- to6-membered heterocycle and is optionally substituted with one or moreR_(A), and preferably, J is at least substituted with a C₃-C₆carbocycleor 3- to 6-membered heterocycle which is independently optionallysubstituted with one or more substituents selected from halogen,hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,thioxo, formyl, cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, C(O)OR_(S) or—N(R_(S)R_(S)′). Also preferably, D is C₅-C₆carbocycle or 5- to6-membered heterocycle and is substituted with J and optionallysubstituted with one or more R_(A), and J is 6- to 12-membered bicycle(e.g., a 7- to 12-membered fused, bridged or spiro bicycle comprising anitrogen ring atom through which J is covalently attached to D) and isoptionally substituted with one or more R_(A). More preferably, D isphenyl and is substituted with J and optionally substituted with one ormore R_(A), and J is C₃-C₆carbocycle, 3- to 6-membered heterocycle or 6-to 12-membered bicycle and is optionally substituted with one or moreR_(A), and preferably J is at least substituted with a C₃-C₆carbocycleor 3- to 6-membered heterocycle which is independently optionallysubstituted with one or more substituents selected from halogen,hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,thioxo, formyl, cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, C(O)OR_(S) or—N(R_(S)R_(S)′). Highly preferably, D is

wherein each R_(N) is independently selected from R_(D) and preferablyis hydrogen or halogen, and J is C₃-C₆carbocycle, 3- to 6-memberedheterocycle or 6- to 12-membered bicycle and is optionally substitutedwith one or more R_(A), and preferably J is at least substituted with aC₃-C₆carbocycle or 3- to 6-membered heterocycle which is independentlyoptionally substituted with one or more substituents selected fromhalogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy,phosphono, thioxo, formyl, cyano, C₁-C₆alkyl, C_(r) C₆alkenyl,C₂-C₆alkynyl, C₁-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl,C(O)OR_(S) or —N(R_(S)R_(S)′). Also preferably, D is

wherein each R_(N) is independently selected from R_(D) and preferablyis hydrogen or halogen, and J is C₃-C₆carbocycle or 3- to 6-memberedheterocycle and is substituted with a C₃-C₆carbocycle or 3- to6-membered heterocycle which is independently optionally substitutedwith one or more substituents selected from halogen, hydroxy, mercapto,amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl,cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl,C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, C(O)OR_(S) or —N(R_(S)R_(S)′), and Jcan also be optionally substituted with one or more R_(A). Alsopreferably, D is

and J is C₃-C₆carbocycle or 3- to 6-membered heterocycle and isoptionally substituted with one or more R_(A), and preferably J is atleast substituted with a C₃-C₆carbocycle or 3- to 6-membered heterocyclewhich is independently optionally substituted with one or moresubstituents selected from halogen, hydroxy, mercapto, amino, carboxy,nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl, C₂-C₆haloalkenyl,C₂-C₆haloalkynyl, C(O)OR_(S) or —N(R_(S)R_(S)′).

X preferably is C₅-C₆carbocycle, 5- to 6-membered heterocycle, or 6- to12-membered bicycles (e.g.,

wherein X₃ is N and is directly linked to -L₃-D), and is optionallysubstituted with one or more R_(A) or R_(F). Non-limiting examples of Xare described hereinabove.

L₁ and L₂ are preferably independently bond or C₁-C₆alkylene, L₃ ispreferably selected from bond, C₁-C₆alkylene or —C(O)—, and L₁, L₂, andL₃ are each independently optionally substituted with one or more R_(L).More preferably, L₁, L₂ and L₃ are each independently bond orC₁-C₆alkylene (e.g., —CH₂— or —CH₂CH₂—), and are each independentlyoptionally substituted with one or more R_(L). Highly preferably, L₁, L₂and L₃ are bond.

R₂ and R₅, taken together with the atoms to which they are attached,preferably form a 5- to 6-membered heterocycle or 6- to 12-memberedbicycle (e.g.,

which is optionally substituted with one or more R_(A).

R₉ and R₁₂, taken together with the atoms to which they are attached,preferably form a 5- to 6-membered heterocycle or 6- to 12-memberedbicycle (e.g.,

which is optionally substituted with one or more R_(A).

G₁ and G₂ preferably are each independently selected from

and are each independently optionally substituted with one or more R_(A)(e.g., one or more chloro or bromo). More preferably, G₁ is

(including any tautomer thereof), and G₂ is

(including any tautomer thereof), and each G₁ and G₂ is independentlyoptionally substituted with one or more R_(A) (e.g., one or more chloroor bromo).

-T-R_(D)′ can be, without limitation, independently selected at eachoccurrence from —C(O)-L_(Y)-C(O)O-L_(Y)′—R_(D)′,—C(O)-L_(Y)′—N(R_(B))C(O)-L_(S)″—R_(D)′,—C(O)-L_(Y)′—N(R_(B))C(O)O-L_(S)″—R_(D)′,—N(R_(B))C(O)-L_(Y)′—N(R_(B))C(O)-L_(S)″—R_(D)′,—N(R_(B))C(O)-L_(Y)′—N(R_(B))C(O)O-L_(S)″—R_(D)′, or—N(R_(B))C(O)-L_(Y)′—N(R_(B))-L_(S)″—R_(D)′, wherein L_(Y)′ is eachindependently L_(S)′ and, preferably, is each independentlyC₁-C₆alkylene (e.g., —CH₂— or

) and optionally substituted with one or more substituents selected fromR_(L). Preferably, -T-R_(D)′ is independently selected at eachoccurrence from —C(O)-L_(Y)′— M′-L_(S)″—R_(D)′ or—N(R_(B))C(O)-L_(Y)′-M′-L_(S)″—R_(D)′. More preferably, -T-R_(D)′ isindependently selected at each occurrence from—C(O)-L_(Y)′—N(R_(B))C(O)-L_(S)″—R_(D)′ or—C(O)-L_(Y)′—N(R_(B))C(O)O-L_(S)″—R_(D)′. Highly preferably, -T-R_(D)′is independently selected at each occurrence from—C(O)-L_(Y)′—N(R_(B))C(O)—R_(D)′ or —C(O)-L_(Y)′—N(R_(B))C(O)O—R_(D)′,wherein L_(Y)′ preferably is each independently C₁-C₆alkylene (e.g.,—CH₂— or

) and optionally substituted with one or more substituents selected fromR_(L).

R_(C)′ is preferably hydrogen, and R_(D)′ preferably is independentlyselected at each occurrence from R_(E). More preferably, R_(D)′ isindependently selected at each occurrence from C₁-C₆alkyl, C₂-C₆alkenylor C₂-C₆alkynyl, each of which is independently optionally substitutedat each occurrence with one or more substituents selected from halogen,hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,thioxo, formyl, cyano, C₃-C₆carbocycle or 3- to 6-membered heterocycle;or C₃-C₆carbocycle or 3- to 6-membered heterocycle, each of which isindependently optionally substituted at each occurrence with one or moresubstituents selected from halogen, hydroxy, mercapto, amino, carboxy,nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl, C₂-C₆haloalkenyl orC₂-C₆haloalkynyl.

R_(A) preferably is halogen, hydroxy, mercapto, amino, carboxy, nitro,oxo, phosphonoxy, phosphono, thioxo, cyano; or C₁-C₆alkyl, C₂-C₆alkenylor C₂-C₆alkynyl, each of which is independently optionally substitutedat each occurrence with one or more substituents selected from halogen,hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,thioxo, formyl or cyano; or C₃-C₆carbocycle or 3- to 6-memberedheterocycle, each of which is independently optionally substituted ateach occurrence with one or more substituents selected from halogen,hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,thioxo, formyl, cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆haloalkyl, C₂-C₆haloalkenyl or C₂-C₆haloalkynyl; or -L_(A)-O—R_(S),-L_(A)-C(O)R_(S), -L_(A)-OC(O)R_(S), -L_(A)-C(O)OR_(S),-L_(A)-N(R_(S)R_(S)′), -L_(A)-S(O)R_(S), -L_(A)-SO₂R_(S),-L_(A)-C(O)N(R_(S)R_(S)′), -L_(A)-N(R_(S))C(O)R_(S)′,-L_(A)-N(R_(S))C(O)N(R_(S)′R_(S)″), -L_(A)-N(R_(S))SO₂R_(S)′,-L_(A)-SO₂N(R_(S)R_(S)′), -L_(A)-N(R_(S))SO₂N(R_(S)′R_(S)″),-L_(A)-N(R_(S))S(O)N(R_(S)′R_(S)″), -L_(A)-OS(O)—R_(S),-L_(A)-OS(O)₂—R_(S), -L_(A)-S(O)₂OR₅, -L_(A)-S(O)OR_(S),-L_(A)-OC(O)OR_(S), -L_(A)-N(R_(S))C(O)OR_(S)′,-L_(A)—OC(O)N(R_(S)R_(S)′), -L_(A)-N(R_(S))S(O)—R_(S)′,-L_(A)-S(O)N(R_(S)R_(S)′) or -L_(A)-C(O)N(R_(S))C(O)—R_(S)′, whereinL_(A) is bond, C₁-C₆alkylene, C₂-C₆alkenylene or C₂-C₆alkynylene.

More preferably, R_(A) is halogen, hydroxy, mercapto, amino, carboxy,nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or C₁-C₆alkyl,C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is independently optionallysubstituted at each occurrence with one or more substituents selectedfrom halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,phosphonoxy, phosphono, thioxo, formyl or cyano; or C₃-C₆carbocycle or3- to 6-membered heterocycle, each of which is independently optionallysubstituted at each occurrence with one or more substituents selectedfrom halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,phosphonoxy, phosphono, thioxo, formyl, cyano, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₁-C₆haloalkyl, C₂-C₆haloalkenyl or C₂-C₆haloalkynyl.

Highly preferably, R_(A) is halogen, hydroxy, mercapto, amino, carboxy,nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or C₁-C₆alkyl,C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is independently optionallysubstituted at each occurrence with one or more substituents selectedfrom halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,phosphonoxy, phosphono, thioxo, formyl or cyano.

L_(S), L_(S)′ and L_(S)″ preferably are each independently selected ateach occurrence from bond; or C₁-C₆alkylene, C₂-C₆alkenylene orC₂-C₆alkynylene.

A and B can be the same or different. Likewise, L₁ and L₂ can be thesame or different.

In one embodiment of this aspect, A and B are each independently phenyl,and are each independently optionally substituted with one or moreR_(A); D is phenyl, and is independently optionally substituted with oneor more R_(A), or is substituted with J and optionally substituted withone or more R_(A), wherein J is C₃-C₆carbocycle, 3- to 6-memberedheterocycle or 6- to 12-membered bicycle and is optionally substitutedwith one or more R_(A). Preferably, J is substituted with aC₃-C₆carbocycle or 3- to 6-membered heterocycle which is independentlyoptionally substituted with one or more substituents selected fromhalogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy,phosphono, thioxo, formyl, cyano, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₁-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl,C(O)OR_(S) or —N(R_(S)R_(S)′), and J can also be optionally substitutedwith one or more R_(A); and G₁ is

G₂ is

and each G₁ and G₂ is independently optionally substituted with one ormore R_(A) (e.g., one or more chloro or bromo). Preferably, D is

wherein R_(M) and R_(N) are as defined above. Also preferably, D is

wherein J and R_(N) are as defined above. L₁ and L₂ are eachindependently bond or C₁-C₆alkylene, and L₃ is bond, C₁-C₆alkylene or—C(O)—, and L₁, L₂, and L₃ are each independently optionally substitutedwith one or more R_(L). Preferably, L₁, L₂, and L₃ are bond. -T-R_(D)′is independently selected at each occurrence from—C(O)-L_(Y)′—N(R_(B))C(O)-L_(S)″—R_(D)′ or—C(O)-L_(Y)′—N(R_(B))C(O)O-L_(S)″—R_(D)′, wherein L_(Y)′ isC₁-C₆alkylene (e.g., —CH₂—) and optionally substituted with one or moresubstituents selected from R_(L), and L_(S)″ preferably is bond.-T-R_(D)′ can also be, without limitation, selected from—C(O)-L_(Y)′-L_(S)″—R_(D)′, —C(O)-L_(Y)′-O-L_(S)″—R_(D)′,—C(O)-L_(Y)′—N(R_(B))— L_(S)″—R_(D)′, or—C(O)-L_(Y)′—N(R_(B))S(O)₂-L_(S)″—R_(D)′. Preferably, R₂ and R₅, takentogether with the atoms to which they are attached, form

which is optionally substituted with one or more R_(A); R₉ and R₁₂,taken together with the atoms to which they are attached, form

which is optionally substituted with one or more R_(A).

In another embodiment of this aspect, A and B are each independentlyphenyl (e.g.,

and are each independently optionally substituted with one or more R_(A)(preferably, A and B are each independently substituted with at leastone halogen such as F). X is

wherein X₃ is N and is directly linked to -L₃-D, and X is optionallysubstituted with one or more R_(A) or R_(E). D is phenyl, and issubstituted with J and optionally substituted with one or more R_(A). Jis C₃-C₆carbocycle, 3- to 6-membered heterocycle, 6- to 12-memberedbicycle, 10- to 15-membered tricycle or 13- to 15-memberedcarbocycle/heterocycle, and J is optionally substituted with one or moreR_(A). Preferably, J is substituted with a C₃-C₆carbocycle, 3- to6-membered heterocycle, 6- to 12-membered bicycle or 7- to 12-memberedcarbocycle/heterocycle, which is independently optionally substitutedwith one or more substituents selected from (1) halogen, hydroxy,mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo,formyl, cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl,C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, —C(O)OR_(S) or —N(R_(S)R_(S)′), or(2) trimethylsilyl, —O—R_(S), —S—R_(S) or —C(O)R_(S); and J can also beoptionally substituted with one or more R_(A). Preferably, D

wherein J is as defined above, and each R_(N) is independently selectedfrom R_(D) and preferably is hydrogen or halo such as F. G₁ is

G₂ is

and each G₁ and G₂ is independently optionally substituted with one ormore R_(A) (e.g., one or more chloro or bromo). L₁ and L₂ are eachindependently bond or C₁-C₆alkylene, and L₃ is bond, C₁-C₆alkylene or—C(O)—, and L₁, L₂, and L₃ are each independently optionally substitutedwith one or more R_(L). Preferably, L₁, L₂, and L₃ are bond. -T-R_(D)′is independently selected at each occurrence from—C(O)-L_(Y)′—N(R_(B))C(O)-L_(S)″—R_(D)′ or—C(O)-L_(Y)′—N(R_(B))C(O)O-L_(S)″—R_(D)′, wherein L_(Y)′ isC₁-C₆alkylene (e.g., —CH₂—) and optionally substituted with one or moresubstituents selected from R_(L), and L_(S)″ preferably is bond.-T-R_(D)′ can also be, without limitation, selected from—C(O)-L_(Y)′-L_(S)″—R_(n)′, —C(O)-L_(Y)′—O-L_(S)″—R_(D)′,—C(O)-L_(Y)′—N(R_(B))-L_(S)″—R_(D)′, or—C(O)-L_(Y)′—N(R_(B))S(O)₂-L_(S)″—R_(D)′. Preferably, R₂ and R₅, takentogether with the atoms to which they are attached, form a 5- to6-membered heterocyclic ring

or 6- to 12-membered bicycle

which is optionally substituted with one or more R_(A); R₉ and R₁₂,taken together with the atoms to which they are attached, form a 5- to6-membered heterocyclic ring

or 6- to 12-membered bicycle

which is optionally substituted with one or more R_(A).

In another aspect, the present invention features compounds havingFormula I_(E) and pharmaceutically acceptable salts thereof,

wherein:

-   -   X is 4- to 8-membered heterocycle, and is optionally substituted        with one or more R_(A);    -   L₁ and L₂ are each independently selected from bond or        C₁-C₆alkylene which is independently optionally substituted at        each occurrence with one or more halo, hydroxy, —O—C₁-C₆alkyl,        or —O—C₁-C₆haloalkyl;    -   L₃ is bond or C₁-C₆alkylene;    -   A and B are each independently phenyl, pyridinyl, thiazolyl, or

where Z₁ is independently selected at each occurrence from O, S, NH orCH₂, Z₃ is independently selected at each occurrence from N or CH, andW₁, W₂, and W₃ are each independently selected at each occurrence fromCH or N; A and B are each independently optionally substituted with oneor more R_(A).

-   -   D is C₆-C₁₀carbocycle or 5- to 12-membered heterocycle, each of        which is optionally substituted with one or more R_(M);    -   Y is -T′—C(R₁R₂)N(R₅)-T—R_(D);    -   Z is -T′—C(R₈R₉)N(R₁₂)-T—R_(D);    -   R₁ is hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, or 3- to 6-membered        carbocycle or heterocycle, wherein each said 3- to 6-membered        carbocycle or heterocycle is independently optionally        substituted at each occurrence with one or more substituents        selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, —O—C₁-C₆alkyl        or —O—C₁-C₆haloalkyl;    -   R₂ and R₅ are each independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, or 3- to 6-membered carbocycle or heterocycle,        wherein each said 3- to 6-membered carbocycle or heterocycle is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, —O—C₁-C₆alkyl or —O—C₁-C₆haloalkyl; or R₂ and        R₅, taken together with the atoms to which they are attached,        form a 3- to 12-membered heterocycle which is optionally        substituted with one or more R_(A) (e.g., 1, 2, 3, or 4 R_(A));    -   R₈ is hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, or 3- to 6-membered        carbocycle or heterocycle, wherein each said 3- to 6-membered        carbocycle or heterocycle is independently optionally        substituted at each occurrence with one or more substituents        selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, —O—C₁-C₆alkyl        or —O—C₁-C₆haloalkyl;    -   R₉ and R₁₂ are each independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, or 3- to 6-membered carbocycle or heterocycle,        wherein each said 3- to 6-membered carbocycle or heterocycle is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, —O—C₁-C₆alkyl or —O—C₁-C₆haloalkyl; or R₉ and        R₁₂, taken together with the atoms to which they are attached,        form a 3- to 12-membered heterocycle which is optionally        substituted with one or more R_(A) (e.g., 1, 2, 3, or 4 R_(A));    -   T is independently selected at each occurrence from bond or        —C(O)-L_(S)′-;    -   T′ is independently selected at each occurrence from bond,        —C(O)N(R_(B))—, —N(R_(B))C(O)—, or 3- to 12-membered        heterocycle, wherein said 3- to 12-membered heterocycle is        independently optionally substituted at each occurrence with one        or more R_(A);    -   R_(D) is each independently selected at each occurrence from        hydrogen or R_(A);    -   R_(A) is independently selected at each occurrence from halogen,        nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, or        -L_(S)-R_(E);    -   R_(B) and R_(B)′ are each independently selected at each        occurrence from hydrogen; or C₁-C₆alkyl which is independently        optionally substituted at each occurrence with one or more        substituents selected from halogen or 3- to 6-membered        carbocycle or heterocycle; or 3- to 6-membered carbocycle or        heterocycle; wherein each 3- to 6-membered carbocycle or        heterocycle in R_(B) or R_(B)′ is independently optionally        substituted at each occurrence with one or more substituents        selected from halogen, hydroxy, C₁-C₆alkyl, C₁-C₆haloalkyl,        —O—C₁-C₆alkyl, or —O—C₁-C₆haloalkyl;    -   R_(E) is independently selected at each occurrence from        —O—R_(S), —S—R_(S), —C(O)R_(S), —OC(O)R_(S), —C(O)OR_(S),        —N(R_(S)R_(S)′), —S(O)R_(S), —SO₂R_(S), —C(O)N(R_(S)R_(S)′),        —N(R_(S))C(O)R_(S)′, —N(R_(S))C(O)N(R_(S)′R_(S)″),        —N(R_(S))SO₂R_(S)′, —SO₂N(R_(S)R_(S)′),        —N(R_(S))SO₂N(R_(S)′R_(S)″), —N(R_(S))S(O)N(R_(S)′R_(S)″),        —OS(O)—R_(S), —OS(O)₂—R_(S), —S(O)₂OR_(S), —S(O)OR_(S),        —OC(O)OR_(S), —N(R_(S))C(O)OR_(S)′, —OC(O)N(R_(S)R_(S)′),        —N(R_(S))S(O)—R_(S)′, —S(O)N(R_(S)R_(S)′),        —C(O)N(R_(S))C(O)—R_(S)′, or ═C(R_(S)R_(S)′); or C₁-C₆alkyl,        C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is independently        optionally substituted at each occurrence with one or more        substituents selected from halogen, hydroxy, mercapto, amino,        carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or        cyano; or C₃-C₁₂carbocycle or 3- to 12-membered heterocycle,        each of which is independently optionally substituted at each        occurrence with one or more substituents selected from halogen,        hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy,        phosphono, thioxo, formyl, cyano, C₁-C₆alkyl, C₂-C₆alkenyl,        C₂-C₆alkynyl, C₁-C₆haloalkyl, C₂-C₆haloalkenyl or        C₂-C₆haloalkynyl;    -   R_(L) is independently selected at each occurrence from halogen,        nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, —O—R_(S),        —S—R₅, —C(O)R_(S), —OC(O)R_(S), —C(O)OR_(S), —N(R_(S)R_(S)′),        —S(O)R_(S), —SO₂R_(S), —C(O)N(R_(S)R_(S)′), or        —N(R_(S))C(O)R_(S)′; or C₃-C₁₂carbocycle or 3- to 12-membered        heterocycle, each of which is independently optionally        substituted at each occurrence with one or more substituents        selected from halogen, hydroxy, mercapto, amino, carboxy, nitro,        oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C₁-C₆alkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl, C₂-C₆haloalkenyl or        C₂-C₆haloalkynyl;    -   L_(S) is independently selected at each occurrence from bond; or        C₁-C₆alkylene, C₂-C₆alkenylene or C₂-C₆alkynylene, each        independently optionally substituted with halogen;    -   L_(S)′ is independently selected at each occurrence from bond;        or C₁-C₆alkylene, C₂-C₆alkenylene or C₂-C₆alkynylene, each of        which is independently optionally substituted at each occurrence        with one or more R_(L);    -   R_(S), R_(S)′ and R_(S)″ are each independently selected at each        occurrence from hydrogen; C₁-C₆alkyl, C₂-C₆alkenyl or        C₂-C₆alkynyl, each of which is independently optionally        substituted at each occurrence with one or more substituents        selected from halogen, hydroxy, mercapto, amino, carboxy, nitro,        oxo, phosphonoxy, phosphono, thioxo, formyl, cyano,        —O—C₁-C₆alkyl, —O—C₁-C₆haloalkyl, or 3- to 12-membered        carbocycle or heterocycle; or 3- to 12-membered carbocycle or        heterocycle; wherein each 3- to 12-membered carbocycle or        heterocycle in R_(S), R_(S)′ or R_(S)″ is independently        optionally substituted at each occurrence with one or more        substituents selected from halogen, hydroxy, mercapto, amino,        carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl,        cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl,        C₂-C₆haloalkenyl or C₂-C₆haloalkynyl;    -   R_(M) is independently selected at each occurrence from:        -   halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,            phosphonoxy, phosphono, thioxo, cyano, SF₅, —N(R_(S)R_(S)′),            —O—R_(S), —OC(O)R_(S), —OC(O)OR_(S), —OC(O)N(R_(S)R_(S)′),            —C(O)R_(S), —C(O)OR_(S), —C(O)N(R_(S)R_(S)′),            —N(R_(S))C(O)R_(S)′, —N(R_(S))C(O)OR_(S)′,            —N(R_(S))SO₂R_(S)′, —S(O)R_(S), —SO₂R_(S),            —S(O)N(R_(S)R_(S)′), —SR_(S), —Si(R_(S))₃, or            —P(O)(OR_(S))₂;        -   C₁-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is            independently optionally substituted at each occurrence with            one or more substituents selected from halogen, hydroxy,            mercapto, amino, carboxy, nitro, oxo, phosphonoxy,            phosphono, thioxo, formyl, cyano, —N(R_(S)R_(S)′), —O—R_(S),            —OC(O)R_(S), —OC(O)OR_(S), —OC(O)N(R_(S)R_(S)′), —C(O)R_(S),            —C(O)OR_(S), —C(O)N(R_(S)R_(S)′), —N(R_(S))C(O)R_(S)′,            —N(R_(S))C(O)OR_(S)′, —N(R_(S))SO₂R_(S)′, —S(O)R₅,            —SO₂R_(S), —S(O)N(R_(S)R_(S)′), —SR_(S), or —P(O)(OR_(S))₂;            or        -   G₂, wherein G₂ is a C₃-C₁₂carbocycle or 3- to 12-membered            heterocycle, each of which is independently optionally            substituted at each occurrence with one or more R_(G2), and            each R_(G2) is independently selected from halogen, hydroxy,            mercapto, amino, carboxy, nitro, oxo, phosphonoxy,            phosphono, thioxo, formyl, cyano, C₁-C₆alkyl, C₂-C₆alkenyl,            C₂-C₆alkynyl, C₁-C₆haloalkyl, C₂-C₆haloalkenyl,            C₂-C₆haloalkynyl, —O—R_(S), —C(O)OR_(S), —C(O)R_(S),            —N(R_(S)R_(S)′), or -L₄-G₃;        -   L₄ is a bond, C₁-C₆alkylene, C₂-C₆alkenylene,            C₂-C₆alkynylene, —O—, —S—, —N(R_(B))—, S(O)₂—, —S(O)—,            —C(O)O—, —OC(O)—, —OC(O)O—, —C(O)N(R_(B))—, —N(R_(B))C(O)—,            —N(R_(B))C(O)O—, —OC(O)N(R_(B))—, —N(R_(B))S(O)—,            —N(R_(B))S(O)₂—, —S(O)N(R_(B))—, —S(O)₂N(R_(B))—,            —N(R_(B))C(O)N(R_(B)′)-, —N(R_(B))SO₂N(R_(B)′)-, or            —N(R_(B))S(O)N(R_(B)′)—;        -   G₃ is a C₃-C₁₂carbocycle or 3- to 12-membered heterocycle,            and is optionally substituted with one or more R_(G3); and        -   R_(G3) is each independently, at each occurrence, halogen,            —C₁-C₆alkyl, —C(O)C₁-C₆alkyl, —C₁-C₆haloalkyl,            —O—C₁-C₆alkyl, —O—C₁-C₆haloalkyl, C₃-C₆carbocycle, or 3- to            6-membered heterocycle.

As described hereinabove for compounds of Formula I_(E) A and B are eachphenyl, pyridinyl, thiazolyl, or

where Z₁ is independently selected at each occurrence from O, S, NH orCH₂, Z₃ is independently selected at each occurrence from N or CH, andW₁, W₂, and W₃ are each independently selected at each occurrence fromCH or N; A and B are each independently optionally substituted with oneor more R_(A).

Preferably, A is selected from phenyl (e.g.,

pyridinyl (e.g.,

thiazolyl (e.g.,

(e.g.,

and is optionally substituted with one or more R_(A).

Preferably, B is selected from phenyl (e.g.,

pyridinyl (e.g.,

thiazolyl (e.g.,

(e.g.,

and is optionally substituted with one or more R_(A).

Highly preferably, both A and B are phenyl (e.g., both A and B are

or A is

and B is

or A is

and B is

or A is

and B is

or A is

and B is

or A is

and B is

wherein each A and B is independently optionally substituted with one ormore R_(A).

In certain embodiments of this aspect of the invention, A and B aresubstituted by one or more R_(A), wherein each R_(A) is independentlyselected from halogen (e.g., fluoro, chloro), L_(S)-R_(E) (where L_(S)is bond and R_(E) is —C₁-C₆alkyl (e.g., methyl), —O—R_(S) (e.g.,—O—C₁-C₆alkyl, —OCH₃), or —C₁-C₆alkyl optionally substituted with one ormore halogen (e.g., —CF₃)), or L_(S)-R_(E) (where L_(S) is C₁-C₆alkyleneand R_(E) is —O—R_(S) (e.g., —C₁-C₆alkyl-O—C₁-C₆alkyl, —CH₂OCH₃)). Forexample, in certain embodiments A is

and B is as defined hereinabove. In certain other embodiments B is

and A is as defined hereinabove. In still other embodiments A is

and B is

As described hereinabove for compounds of Formula I_(E) D isC₆-C₁₀carbocycle or 3- to 12-membered heterocycle optionally substitutedby one or more R_(M). Preferably, D is C₆-C₁₀aryl (e.g., phenyl,naphthyl, indanyl), or 5- to 10-membered heteroaryl (pyridinyl,thiazolyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl,indazolyl, benzo[d][1,3]dioxol-5-yl), and D, is substituted with one ormore R_(M). For example, in certain embodiments D is preferably phenylsubstituted by one or more R_(M), wherein each R_(M) is independentlyhalogen (e.g., fluoro, chloro, bromo); C₁-C₆alkyl (e.g., tert-butyl);C₁-C₆alkyl substituted with one or more halogen (e.g., CF₃); —O—R_(S)such as —O—C₁-C₆alkyl (e.g., —O—CH₂CH₃); or —O—C₁-C₆alkyl substituted ateach occurrence with one or more halogen (e.g., —O—CF₃, —O—CH₂CHF₂) or—O—C₁-C₆alkyl (e.g., —O—CH₂CH₂OCH₃); —O—R_(S) (e.g., —O—C₁-C₆alkyl, suchas —O—CH₂) substituted with 3- to 12-membered heterocycle (e.g.,3-ethyloxetane-3-yl, 1,3-dioxolan-4-yl); —O—R_(S) where R_(S) is anoptionally substituted 3- to 12-membered carbocycle or heterocycle(e.g., cyclopentyl, cyclohexyl, phenyl, 1,3-dioxan-5-yl);—N(R_(S))C(O)R_(S)′ wherein R_(S) and R_(S)′ are each independentlyC₁-C₆alkyl (e.g., —N(t-Bu)C(O)Me); SF₅; —SO₂R_(S) wherein R_(S) isC₁-C₆alkyl (e.g., —SO₂Me); or C₃-C₁₂carbocycle (e.g., cyclopropyl,cyclohexyl, phenyl).

In certain embodiments of this aspect of the invention, D is preferablyphenyl or pyridyl and is substituted by one or more R_(M) where oneR_(M) is G₂. In certain embodiments where D is phenyl or pyridyl, D issubstituted by O₂, G₂ is 3- to 12-membered heterocycle (e.g., pyridinyl,piperidinyl, pyrrolidinyl, azetidinyl, oxazolyl) and is optionallysubstituted with one or more halogen (e.g., fluoro, chloro), hydroxy,oxo, cyano, C₁-C₆alkyl (e.g., methyl), C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆haloalkyl (e.g., CF₃), C₂-C₆haloalkenyl, C₂-C₆haloalkynyl,—O—C₁-C₆alkyl (e.g., —O—CH₃), —C(O)OR_(S) (e.g., —C(O)OCH₃), —C(O)R_(S)(e.g., —C(O)CH₃), or —N(R_(S)R_(S)′); and D is further optionallysubstituted by one or more R_(M) where R_(M) is halogen (e.g., fluoro,chloro), C₁-C₆alkyl (e.g., methyl), C₁-C₆haloalkyl (e.g., CF₃), or—O—C₁-C₆alkyl (e.g., —O—CH₃). In certain other embodiments D is phenylor pyridyl and O₂ is, for example, a monocyclic 3-8 membered carbocycleor monocyclic 4-8 membered heterocycle substituted with L₄-G₃ andoptionally substituted with one or more R_(G2) wherein L₄, G₃ and R_(G2)are as defined herein. L₄, for example is a bond, a C₁-C₆ alkylene(e.g., —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, etc.), —O—, or —S(O)₂—. G₃ is forexample a C₃-C₁₂carbocycle optionally substituted with one or moreR_(G3). R_(G2) and R_(G3) are each independently at each occurrencehalogen, —C(O)C₁-C₆alkyl, —C₁-C₆alkyl, —C₁-C₆haloalkyl, —O—C₁-C₆alkyl,or —O—C₁-C₆haloalkyl. In certain embodiments O₂ is

wherein

is a monocyclic 4-8 membered nitrogen-containing heterocycle (e.g.,azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl) attached to theparent molecular moiety through a nitrogen atom and substituted with oneor two L₄-G₃ and optionally substituted with one or more R_(G2). Thus,in certain embodiments where L₄ is a bond G₂ is

where

is optionally substituted with R_(G2) and G₃ is optionally substitutedwith R_(G3). Thus,

can be, for example, 3-phenylazetidin-1-yl, 3-phenylpyrrolidin-1-yl,4-phenylpiperazin-1-yl, 4-phenylpiperidin-1-yl,4-phenyl-3,6-dihydropyridin-1(2H)-yl, 4,4-diphenylpiperidin-1-yl,1,4-acetyl-4-phenylpiperidin-1-yl, 4-(4-methoxyphenyl)piperidin-1-yl,4-(4-fluorophenyl)piperidin-1-yl, or 3-phenylpiperidin-1-yl, and whereinD can be further optionally substituted with one or more R_(M) (e.g.,fluoro, chloro, methyl, methoxy).

In certain other embodiments of this aspect of the invention, L₄ is aC₁-C₆ alkylene, —O—, or —S(O)₂—, and G₂ is

where

is as defined above and is optionally substituted with R_(G2) and G₃ isas defined above and is optionally substituted with R_(G3). Thus,

can be, for example, 4-tosylpiperazin-1-yl, 4-phenoxypiperidin-1-yl,3-phenoxypyrrolidin-1-yl, 4-benzylpiperidin-1-yl,4-phenethylpiperidin-1-yl, or 3-phenylpropyl)piperidin-1-yl.

In certain other embodiments of this aspect of the invention, D isphenyl or pyridyl, D is substituted by G₂ and G₂ is a spiro, bridged, orfused bicyclic carbocycle or heterocycle optionally substituted withL₄-G₃ and one or more R_(G2), wherein D is optionally substituted withone or more R_(M) and R_(M), L₄, G₃, and R_(G2) are as defined herein.In certain embodiments G₂ is

wherein

is a spiro, bridged, or fused bicyclic nitrogen-containing heterocycle(e.g., 3-azabicyclo[3.2.0]hept-3-yl, 2-azabicyclo[2.2.2]oct-2-yl,6-azaspiro[2.5]oct-6-yl, octahydro-2H-isoindol-2-yl,3-azaspiro[5.5]undec-3-yl, 1,3-dihydro-2H-isoindol-2-yl,1,4-dioxa-8-azaspiro[4.5]dec-8-yl) attached to the parent molecularmoiety through a nitrogen atom and optionally substituted with G₃ andone or more R_(G2). Thus, G₂ is 3-azabicyclo[3.2.0]hept-3-yl,2-azabicyclo[2.2.2]oct-2-yl, 6-azaspiro[2.5]oct-6-yl,octahydro-2H-isoindol-2-yl, 3-azaspiro[5.5]undec-3-yl,1,3-dihydro-2H-isoindol-2-yl, or 1,4-dioxa-8-azaspiro[4.5]dec-8-yl; L₄is a bond and D is optionally substituted with one or more R_(M) (e.g.,fluoro, chloro, methyl, methoxy).

In certain embodiments of this aspect of the invention, D is

wherein R_(M) is as defined above in connection with Formula I_(E), andD is optionally substituted by one or more additional R_(M). Forinstance, where D is

R_(M) can be fluoro, chloro, tert-butyl, —O—CH₂CH₃, —O—CF₃, —O—CH₂CHF₂,—O—CH₂CH₂OCH₃, —O—CH₂—(3-ethyloxetan-3-yl), —O—CH₂—(1,3-dioxolan-4-yl),—O—cyclopentyl, —O-cyclohexyl, —O-phenyl, —O—(1,3-dioxan-5-yl),cyclopropyl, cyclohexyl, phenyl, SF₅, —SO₂Me, or —N(t-Bu)C(O)Me and Dcan be optionally substituted by one or more additional R_(M) selectedfrom the group consisting of halogen (e.g., fluoro, chloro) andC₁-C₆alkyl (e.g., methyl).

In certain embodiments, D is

wherein R_(M) is fluoro, chloro, tert-butyl, —O—CH₂CH₃, —O—CF₃,—O—CH₂CHF₂, —O—CH₂CH₂OCH₃, SF₅, —SO₂Me, or —N(t-Bu)C(O)Me and D isoptionally substituted by one or more additional R_(M) selected from thegroup consisting of halogen (e.g., fluoro, chloro) and C₁-C₆alkyl (e.g.,methyl).

In certain embodiments, D is

wherein R_(M) is cyclopropyl, cyclohexyl, or phenyl and D is optionallysubstituted by one or more additional R_(M) selected from the groupconsisting of halogen (e.g., fluoro, chloro) and C₁-C₆alkyl (e.g.,methyl).

In certain embodiments, D is

wherein R_(M) is —O—CH₂—(3-ethyloxetan-3-yl),—O—CH₂—(1,3-dioxolan-4-yl), —O-cyclopentyl, —O-cyclohexyl, —O-phenyl, or—O—(1,3-dioxan-5-yl) and D is optionally substituted by one or moreadditional R_(M) selected from the group consisting of halogen (e.g.,fluoro, chloro) and C₁-C₆alkyl (e.g., methyl).

In certain embodiments, D is

wherein G₂ is pyridinyl (e.g., pyridin-2-yl), piperidin-1-yl,4,4-dimethylpiperidin-1-yl, 4,4-difluoropiperidin-1-yl,2,6-dimethylpiperidin-1-yl, 4-(propan-2-yl)piperidin-1-yl,4-fluoropiperidin-1-yl, 3,5-dimethylpiperidin-1-yl,4-(trifluoromethyl)piperidin-1-yl, 4-methylpiperidin-1-yl,4-tert-butylpiperidin-1-yl, 2-oxopiperidin-1-yl,3,3-dimethylazetidin-1-yl, or oxazolyl (e.g., 1,3-oxazol-2-yl) and D isoptionally substituted by one or more additional R_(M) selected from thegroup consisting of halogen (e.g., fluoro, chloro) and C₁-C₆alkyl (e.g.,methyl).

In another embodiment of this aspect of the invention, D is

wherein G₁ is N, C—H, or C—R_(M); G₂ is

wherein

is a monocyclic 4-8 membered nitrogen-containing heterocycle (e.g.,azetidinyl, pyrrolidinyl, piperidinyl) attached to the parent molecularmoiety through a nitrogen atom and substituted by L₄-G₃ and optionallysubstituted with one or more R_(G2), L₄ is a bond, C₁-C₆ alkylene, —O—,or —S(O)₂—; G₃ is aryl (e.g., phenyl), cycloalkyl (e.g., cyclohexyl), orheterocycle (e.g., thienyl) wherein each G₃ is optionally substitutedwith one or more R_(G3); R_(G2) and R_(G3) at each occurrence are eachindependently halogen, —C(O)C₁-C₆alkyl, —C₁-C₆alkyl, —C₁-C₆haloalkyl,—O—C₁-C₆alkyl, or —O—C₁-C₆haloalkyl; g is 0, 1, 2, or 3; and R_(M) is asdefined above in connection with Formula I_(E). In one group ofcompounds according to this embodiment, D is

wherein G₃ is phenyl optionally substituted with one or two R_(G3); g is0, 1, or 2; R_(M) is each independently fluoro, chloro, methyl, methoxy,trifluoromethyl, or trifluoromethoxy; and

R_(G3) are as defined above. In a further subgroup of compounds of thisembodiment, D is

wherein G₃ is phenyl optionally substituted with one or two R_(G3);R_(M1) is each independently hydrogen, fluoro, chloro, or methyl; andR_(G2) is an optional substituent as described herein. In another groupof compounds according to this embodiment, D is

wherein L₄ is C₁-C₆ alkylene, —O—, or —S(O)₂—; G₃ is phenyl optionallysubstituted with one or two R_(G3); g is 0, 1, or 2; R_(M) is eachindependently fluoro, chloro, methyl, methoxy, trifluoromethyl, ortrifluoromethoxy; and

and R_(G3) are as defined above.

In yet another embodiment of this aspect of the invention, D is

wherein G₁ is N, C—H, or C—R_(M); G₂ is

wherein

is a spiro, bridged, or fused bicyclic nitrogen-containing heterocycle(e.g., 3-azabicyclo[3.2.0]hept-3-yl, 2-azabicyclo[2.2.2]oct-2-yl,6-azaspiro[2.5]oct-6-yl, octahydro-2H-isoindol-2-yl,3-azaspiro[5.5]undec-3-yl, 1,3-dihydro-2H-isoindol-2-yl,1,4-dioxa-8-azaspiro[4.5]dec-8-yl) attached to the parent molecularmoiety through a nitrogen atom and optionally substituted with L₄-G₃ andone or more R_(G2); L₄ is a bond, C₁-C₆ alkylene, —O—, or —S(O)₂—; G₃ isaryl (e.g., phenyl), cycloalkyl (e.g., cyclohexyl), or heterocycle(e.g., thienyl) wherein each G₃ is optionally substituted with one ormore R_(G3); R_(G2) and R_(G3) at each occurrence are each independentlyhalogen, —C(O)C₁-C₆alkyl, —C₁-C₆alkyl, —C₁-C₆haloalkyl, —O—C₁-C₆alkyl,or —O—C₁-C₆haloalkyl; g is 0, 1, 2, or 3; and R_(M) is as defined abovein connection with Formula I_(E). In one group of compounds according tothis embodiment, D is

wherein g is 0, 1, or 2; R_(M) is each independently fluoro, chloro,methyl, methoxy, trifluoromethyl, or trifluoromethoxy; and

is as defined above. In a further subgroup of compounds D is

wherein R_(M1) is each independently hydrogen, fluoro, chloro, ormethyl, and

is as defined above (e.g., 3-azabicyclo[3.2.0]hept-3-yl,octahydro-2H-isoindol-2-yl, 2-azabicyclo[2.2.2]oct-2-yl,6-azaspiro[2.5]oct-6-yl, 3-azaspiro[5.5]undec-3-yl,1,3-dihydro-2H-isoindol-2-yl, 1,4-dioxa-8-azaspiro[4.5]dec-8-yl).

In still another embodiment of this aspect of the invention, D is

wherein

is a monocyclic 4-8 membered nitrogen-containing heterocycle (e.g.,azetidinyl, pyrrolidinyl, piperidinyl) substituted with one or moreR_(G2), wherein R_(G2) at each occurrence is each independently halogen,—C(O)C₁-C₆alkyl, —C₁-C₆alkyl, —C₁-C₆haloalkyl, —O—C₁-C₆alkyl, or—O—C₁-C₆haloalkyl; and R_(M) is each independently halogen, —C₁-C₆alkyl,—C₁-C₆haloalkyl, —O—C₁-C₆alkyl, or —O—C₁-C₆haloalkyl. In one group ofcompounds according to this embodiment,

is azetidinyl, pyrrolidinyl, or piperidinyl substituted with one or twoR_(G2), wherein R_(G2) at each occurrence is each independently methyl,ethyl, isopropyl, tert-butyl, fluoro, chloro, or trifluoromethyl; andR_(M) is each independently fluoro, chloro, or methyl. For example

is 4,4-dimethylpiperidin-1-yl, 4,4-difluoropiperidin-1-yl,2,6-dimethylpiperidin-1-yl, 4-(propan-2-yl)piperidin-1-yl,4-fluoropiperidin-1-yl, 3,5-dimethylpiperidin-1-yl,4-(trifluoromethyl)piperidin-1-yl, 4-methylpiperidin-1-yl,4-tert-butylpiperidin-1-yl, 2-oxopiperidin-1-yl, or3,3-dimethylazetidin-1-yl.

For compounds of Formula I_(E)

attachment of X to the remainder of the molecule can be convenientlydepicted by the abbreviated structural Formula X′, wherein the groupsattached to X maintain the same relative spatial orientation as drawn inFormula I_(E) It is understood that in subsequent depictions of thevariable group X, the substituents of X will retain the same relativepositions and orientation as in Formula I_(E) and Formula X′.

Compounds of Formula I_(E) include those where the variable X isselected from the group consisting of X-1, X-2, X-3, and X-4 whereinX-1, X-2, X-3, and X-4 retain the same orientation as structure X′relative to the remainder of the molecule; wherein the presence of

in X-1, X-2, and X-3 represents single or double bonds, X₁ isC₁-C₂alkylene or C₂alkenylene, X₂ and X₃ are each C₁-C₂alkylene orC₂alkenylene, and X₄ is C₁-C₂ alkylene.

In accordance with the foregoing description, in certain embodiments ofthis aspect of the invention, X is pyrrolyl and is attached to theremainder of the molecule as shown in Formula X_(A):

In certain embodiments, X is pyrrolidinyl and is attached to theremainder of the molecule as shown in Formula X_(B):

Embodiments according to Formula X_(B) may exist in cis (X_(B1)) ortrans (X_(B2)) forms:

Chiral carbon atoms in X_(B), X_(B1), and X_(B2) may have either the (R)or (S) absolute stereochemistry.

In yet another embodiment of this aspect of the invention, X is pyrrolyland is attached to the remainder of the molecule as shown in FormulaeX_(C1) or X_(C2):

In certain embodiments, X is pyrrolidinyl and is attached to theremainder of the molecule as shown in Formulae X_(D), or X_(D2):

Embodiments according to Formulae X_(D1) or X_(D2) may exist in cis ortrans forms and chiral carbon atoms in X_(D), and X_(D2) may have eitherthe (R) or (S) absolute stereochemistry. In certain embodiments, X isazetidinyl and is attached to the remainder of the molecule as shown inFormulae X_(E1) or X_(E2):

Chiral carbon atoms in X_(E1) and X_(E2) may independently have eitherthe (R) or (S) absolute stereochemistry.

In certain preferred embodiments of this aspect of the invention, X isX_(A), X_(B), X_(B1), X_(B2), X_(C1), or X_(C2) and L₁, L₂, and L₃ areeach a bond. In certain other embodiments, X is X_(D1), X_(D2), X_(E1),or X_(E2) and L₁, L₂, and L₃ are each a bond. In another embodiment, Xis X_(E1) and L₁ and L₂ are each methylene (i.e. —CH₂—), and L₃ is abond.

In compounds of Formula I_(E), Y is -T′—C(R₁R₂)N(R₅)-T—R_(D) and Z is-T′—C(R₈R₉)N(R₁₂)-T—R_(D); wherein T′, R₁, R₂, R₅, R₈, R₉, R₁₂, T, andR_(D) are as defined herein.

Preferably R₁, R₂, R₅, R₈, R₉, and R₁₂ are each independently hydrogen;C₁-C₆alkyl; or 3- to 6-membered carbocycle or heterocycle, wherein each3- to 6-membered carbocycle or heterocycle is independently optionallysubstituted at each occurrence with one or more substituents selectedfrom halogen or C₁-C₆alkyl; wherein R₂ and R₅, taken together with theatoms to which they are attached, optionally form a 3- to 12-memberedheterocycle which is substituted with 0, 1, 2, 3, or 4 R_(A), and R₉ andR₁₂ taken together with the atoms to which they are attached, optionallyform a 3- to 12-membered heterocycle which is substituted with 0, 1, 2,3, or 4 R_(A) wherein R_(A) is as defined herein.

In certain embodiments of this aspect of the invention, R₁ is hydrogenand R₂ and R₅, taken together with the atoms to which they are attachedform a 3- to 12-membered heterocycle (e.g.,

substituted with 0, 1, 2, 3, or 4 R_(A) wherein R_(A) is halogen (e.g.,fluoro, chloro); cyano; L_(S)-R_(E) where L_(S) is a single bond andR_(E) is C₁-C₆alkyl (e.g., methyl, ethyl), —O—C₁-C₆alkyl (e.g.,methoxy), or —O—C₁-C₆haloalkyl (e.g., trifluoromethoxy); or L_(S)-R_(E)where L_(S) is a double bond and R_(E) is ═C(R_(S)R_(S)′) (e.g.,

In a preferred embodiment R₂ and R₅, taken together with the atoms towhich they are attached form a pyrrolidine ring (i.e.,

substituted with 0 or 1 R_(A) wherein R_(A) is fluoro, methoxy, methyl,ethyl, or cyano. In another preferred embodiment R₂ and R₅, takentogether with the atoms to which they are attached form a pyrrolidinering (i.e.,

In certain other embodiments of this aspect of the invention, R₈ ishydrogen and R₉ and R₁₂, taken together with the atoms to which they areattached form a 3- to 12-membered heterocycle (e.g.,

substituted with 0, 1, 2, 3, or 4 R_(A) wherein R_(A) is halogen (e.g.,fluoro, chloro); cyano; L_(S)-R_(E) where L_(S) is a single bond andR_(E) is C₁-C₆alkyl (e.g., methyl, ethyl), —O—C₁-C₆alkyl (e.g.,methoxy), or —O—C₁-C₆haloalkyl (e.g., trifluoromethoxy); or L_(S)-R_(E)where L_(S) is a double bond and R_(E) is ═C(R_(S)R_(S)′) (e.g.,

In a preferred embodiment, R₉ and R₁₂, taken together with the atoms towhich they are attached form a pyrrolidine ring (i.e.,

substituted with 0 or 1 R_(A) wherein R_(A) is fluoro, methoxy, methyl,ethyl, or cyano. In another preferred embodiment R₉ and R₁₂, takentogether with the atoms to which they are attached form a pyrrolidinering (i.e.,

As used herein, a chiral carbon in any rings formed by joining R₂ and R₅or R₉ and R₁₂ may possess either (R) or (S) stereochemistry. Apyrrolidine ring (i.e.,

formed from either R₂ and R₅ or R₉ and R₁₂ preferably possesses the (S)stereochemistry (i.e.,

In this aspect of the invention, T′ is independently selected at eachoccurrence from a bond, —C(O)N(R_(B))—, —N(R_(B))C(O)—, or 3- to12-membered heterocycle, and wherein said 3- to 12-membered heterocycleis each independently optionally substituted at each occurrence with oneor more R_(A), and R_(A) and R_(B) are as described herein. Inparticular, where T′ is —C(O)N(R_(B))—, R_(B) can be hydrogen (i.e., T′is —C(O)N(H)—). In certain embodiments, T′ is imidazolyl (i.e.,

optionally substituted at each occurrence with one or more R_(A) whereinR_(A) is halogen (e.g., fluoro, chloro), C₁-C₆alkyl (e.g., methyl,ethyl), or C₁-C₆haloalkyl (e.g., trifluoromethyl). In certainembodiments, T′ is imidazolyl (i.e.

This aspect of the invention contemplates particular combinations of Awith Y and B with Z. Non-limiting examples of preferred Y when A isC₅-C₆carbocycle (e.g., phenyl) or 5- to 6-membered heterocycle (e.g.,pyridinyl or thiazolyl) and preferred Z when B is C₅-C₆carbocycle (e.g.,phenyl) or 5- to 6-membered heterocycle (e.g., pyridinyl or thiazolyl)include:

wherein T and R_(D) are as defined herein.

In certain embodiments of this aspect of the invention, A is

optionally substituted with one or more R_(A) as described herein, orY-A is

and non-limiting examples of preferred Y, where T′ is a bond, include:

wherein T and R_(D) are as defined herein.

In certain embodiments of this aspect of the invention, B is

optionally substituted with one or more R_(A) as described herein, orB—Z is

and non-limiting examples of preferred Z, where T′ is a bond, include:

wherein T and R_(D) are as defined herein.

T at each occurrence is independently a bond or —C(O)-L_(S)′-, whereinL_(S)′ is as defined herein. L_(S)′ includes, but is not limited to,

where L_(S)′ is optionally substituted with one or more R_(L); and R_(L)is a substituent such as, but not limited to carbocycle (e.g.,cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, phenyl), methoxy, orheterocycle (e.g., tetrahydrofuranyl, tetrahydropyranyl).

R_(D) is hydrogen or R_(A) wherein R_(A) is as defined herein. ThusR_(D) includes, but is not limited to, R_(A) wherein R_(A) isL_(S)-R_(E), and L_(S) and R_(E) are as defined herein. Thus R_(D)includes, but is not limited to, L_(S)-R_(E) wherein L_(S) is a bond andR_(E) is —N(R_(S)R_(S)′), —N(R_(S))C(O)R_(S)′,—N(R_(S))C(O)N(R_(S)′R_(S)″), —N(R_(S))SO₂R_(S)′,—N(R_(S))SO₂N(R_(S)′R_(S)″), —N(R_(S))S(O)N(R_(S)′R_(S)″),—N(R_(S))C(O)OR_(S)′, or —N(R_(S))S(O)—R_(S)′; or C₃-C₁₂carbocycle or 3-to 12-membered heterocycle, each of which is independently optionallysubstituted at each occurrence with one or more substituents selectedfrom halogen, hydroxy, cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, orC₁-C₆haloalkyl.

In one embodiment of this aspect of the invention, R_(D) is L_(S)-R_(E)wherein L_(S) is a bond and R_(E) is —N(R_(S))C(O)OR_(S)′ or 3- to12-membered heterocycle (e.g., pyrrolidine, piperidine, azepanyl)wherein R_(S) and R_(S)′ are as defined herein. For example R_(D) ispreferably L_(S)-R_(E) wherein L_(S) is a bond and R_(E) is—N(H)C(O)OMe.

Thus according to the foregoing description T-R_(D) includes, but is notlimited to:

T-R_(D) may also include particular stereochemical configurations; thusT-R_(D) includes, but is not limited to:

etc.

According to this aspect of the invention, non-limiting examples ofpreferred Y when A is C₅-C₆carbocycle (e.g., phenyl) or 5- to 6-memberedheterocycle (e.g., pyridinyl or thiazolyl) and preferred Z when B isC₅-C₆carbocycle (e.g., phenyl) or 5- to 6-membered heterocycle (e.g.,pyridinyl or thiazolyl) include:

Non-limiting examples of preferred Y when A is

optionally substituted with one or more R_(A) as described herein, andY-A is

include:

Non-limiting examples of preferred Z where B is

optionally substituted with one or more R_(A) as described herein, andB—Z is

include:

In still another aspect, the present invention features compounds ofFormula I_(F) and pharmaceutically acceptable salts thereof:

wherein:

X is

wherein X is optionally substituted with one or more R_(A)

A is

wherein A is optionally substituted with one or more R_(A);

B is

wherein B is optionally substituted with one or more R_(A); and

-   -   Y, Z, R_(A), and D are as described hereinabove (e.g., Y, Z,        R_(A), and D as described for Formula I, I_(A), I_(B), I_(C),        I_(D), or T_(E), preferably as described for Formula I_(E)).

In one embodiment of this aspect of the invention, X is

A is

wherein A is optionally substituted with one or more R_(A); B is

wherein B is optionally substituted with one or more R_(A); Y is

and D, R_(A), T and R_(D) are as defined hereinabove (e.g., as describedfor Formula I, I_(A), I_(B), I_(C), I_(D) or I_(E), preferably asdescribed for Formula I_(E)).

In another embodiment according to this aspect of the invention, A or Bare optionally substituted with one or more substituents selected from:R_(A) wherein R_(A) is each independently halogen (e.g., fluoro,chloro); L_(S)-R_(E) where L_(S) is a single bond, and R_(E) is—C₁-C₆alkyl (e.g., methyl), —O—R_(S) (e.g., —O—C₁-C₆alkyl, —OCH₃), or—C₁-C₆alkyl optionally substituted with one or more halogen (e.g.,—CF₃); or L_(S)-R_(E) where L_(S) is a C₁-C₆alkylene and R_(E) is—O—R_(S) (e.g., —C₁-C₆alkyl-O—C₁-C₆alkyl, —CH₂OCH₃). This embodimentincludes compounds where A and B are both substituted by one R_(A);compounds where A and B are both substituted by zero R_(A); compoundswhere A is substituted by one R_(A) and B is substituted by zero R_(A);and compounds where A is substituted by zero R_(A) and B is substitutedby one R_(A). Preferably, A is

and B is

or A is

and B is

or A is

and B is

or A is

and B is

In a further embodiment of this aspect of the invention, T—R_(D) isindependently selected at each occurrence from the group consisting of

wherein compounds having (S) stereochemistry (e.g.,

are preferred and wherein D is as defined hereinabove.

In another embodiment, this aspect of the invention features compound ofFormula I_(F) and pharmaceutically acceptable salts thereof, wherein:

X is

A is

wherein A is optionally substituted with one or more R_(A); B is

wherein B is optionally substituted with one or more R_(A); Y is

and D, R_(A), T and R_(D) are as defined hereinabove. A particularsubgroup according to this embodiment includes compounds where A is

B is

Y is

Z is

T—R_(D) is each independently

and D is as defined hereinabove.

In yet another embodiment, this aspect of the invention featurescompounds of Formula I_(F) and pharmaceutically acceptable saltsthereof, wherein: X is

A and B are each

Y and Z are each independently

and D, T and R_(D) are as defined hereinabove. A particular subgroupaccording to this embodiment includes compounds where T—R_(D) is eachindependently selected from

and D is as defined hereinabove.

According to each of the foregoing embodiments and description of thisaspect of the invention of Formula I_(F) are groups and subgroups ofcompounds having particular values for D. Included in each of theforegoing embodiments are groups and subgroups of compounds with thefollowing particular values for D:

In certain groups of compounds according to Formula I_(F) and theforegoing embodiments and description of this aspect of the invention, Dis

where R_(M) is fluoro, chloro, tert-butyl, —O—CH₂CH₃, —O—CF₃,—O—CH₂CHF₂, —O—CH₂CH₂OCH₃, —O—CH₂—(3-ethyloxetan-3-yl),—O—CH₂—(1,3-dioxolan-4-yl), —O-cyclopentyl, —O-cyclohexyl, —O-phenyl,—O—(1,3-dioxan-5-yl), cyclopropyl, cyclohexyl, phenyl, SF₅, —SO₂Me, or—N(t-Bu)C(O)Me and D is optionally substituted by one or more additionalR_(M), selected from the group consisting of halogen (e.g., fluoro,chloro) or C₁-C₆alkyl (e.g., methyl).

In other groups of compounds according Formula I_(F) and the foregoingembodiments and description of this aspect of the invention, D is

wherein G₂ is pyridinyl (e.g., pyridin-2-yl), piperidin-1-yl,4,4-dimethylpiperidin-1-yl, 4,4-difluoropiperidin-1-yl,2,6-dimethylpiperidin-1-yl, 4-(propan-2-yl)piperidin-1-yl,4-fluoropiperidin-1-yl, 3,5-dimethylpiperidin-1-yl,4-(trifluoromethyl)piperidin-1-yl, 4-methylpiperidin-1-yl,4-tert-butylpiperidin-1-yl, 2-oxopiperidin-1-yl,3,3-dimethylazetidin-1-yl, or oxazolyl (e.g., 1,3-oxazol-2-yl) and D isoptionally substituted by one or more additional R_(M) selected from thegroup consisting of halogen (e.g., fluoro, chloro), or C₁-C₆alkyl (e.g.,methyl). In particular according to these groups are compounds where Dis

G₂ is piperidin-1-yl, 4,4-dimethylpiperidin-1-yl,4,4-difluoropiperidin-1-yl, 2,6-dimethylpiperidin-1-yl,4-(propan-2-yl)piperidin-1-yl, 4-fluoropiperidin-1-yl,3,5-dimethylpiperidin-1-yl, 4-(trifluoromethyl)piperidin-1-yl,4-methylpiperidin-1-yl, 4-tert-butylpiperidin-1-yl, 2-oxopiperidin-1-yl,or 3,3-dimethylazetidin-1-yl; and R_(M1) is each independently hydrogen,fluoro, chloro, or methyl.

In other groups of compounds according Formula I_(F) and the foregoingembodiments and description of this aspect of the invention, D is

wherein G₁ is N, C—H, or C—R_(M); G₂ is

wherein

R_(M), and g are as defined hereinabove. In particular according tothese groups, R_(M) is each independently fluoro, chloro, methyl,methoxy, trifluoromethyl, or trifluoromethoxy; g is 0, 1, or 2; and

is as defined hereinabove. In further subgroups L₄ is a bond; G₂ is

R_(M) is each independently fluoro, chloro, methyl, methoxy,trifluoromethyl, or trifluoromethoxy; and g is 0, 1, or 2. In particularsubgroups,

is 3-phenylazetidin-1-yl, 3-phenylpyrrolidin-1-yl,4-phenylpiperazin-1-yl, 4-phenylpiperidin-1-yl,4-phenyl-3,6-dihydropyridin-1(2H)-yl, 4,4-diphenylpiperidin-1-yl,4-acetyl-4-phenylpiperidin-1-yl, 4-(4-methoxyphenyl)piperidin-1-yl,4-(4-fluorophenyl)piperidin-1-yl, or 3-phenylpiperidin-1-yl; R_(M) iseach independently fluoro, chloro, methyl, methoxy, trifluoromethyl, ortrifluoromethoxy; and g is 0, 1, or 2. In other subgroups L₄ is C₁-C₆alkylene, —O—, or —S(O)₂—; G₂ is

R_(M) is each independently fluoro, chloro, methyl, methoxy,trifluoromethyl, or trifluoromethoxy; and g is 0, 1, or 2. In particularsubgroups,

is 4-tolylpiperazin-1-yl, 4-phenoxypiperidin-1-yl,3-phenoxypyrrolidin-1-yl, 4-benzylpiperidin-1-yl,4-phenethylpiperidin-1-yl, or 3-phenylpropyl)piperidin-1-yl; R_(M) iseach independently fluoro, chloro, methyl, methoxy, trifluoromethyl, ortrifluoromethoxy; and g is 0, 1, or 2. In further subgroups of compoundsD is

wherein G₃ is phenyl optionally substituted with one or two R_(G3); g is0, 1, or 2; R_(M) is each independently fluoro, chloro, methyl, methoxy,trifluoromethyl, or trifluoromethoxy; and

and R_(G3) are as defined above. In other groups of compounds D is

wherein L₄ is C₁-C₆ alkylene, —O—, or —S(O)₂—; G₃ is phenyl optionallysubstituted with one or two R_(G3); g is 0, 1, or 2; R_(M) is eachindependently fluoro, chloro, methyl, methoxy, trifluoromethyl, ortrifluoromethoxy; and

R_(G3) are as defined above. In further subgroups of compounds D is

wherein G₃ is phenyl optionally substituted with one or two R_(G3) asdefined hereinabove; R_(M1) is each independently hydrogen, fluoro,chloro, or methyl; and R_(G2) is an optional substituent, as describedabove, selected from the group consisting of —C(O)C₁-C₆alkyl,—C₁-C₆alkyl, —C₁-C₆haloalkyl, —O—C₁-C₆alkyl, and —O—C₁-C₆haloalkyl.

In other groups of compounds according Formula I_(F) and the foregoingembodiments and description of this aspect of the invention, D is

wherein G₁ is N, C—H, or C—R_(M); G₂ is

wherein

R_(M), and g are as defined hereinabove. In particular according tothese subgroups, R_(M) is each independently fluoro, chloro, methyl,methoxy, trifluoromethyl, or trifluoromethoxy; g is 0, 1, or 2; and

is 3-azabicyclo[3.2.0]hept-3-yl, 2-azabicyclo[2.2.2]oct-2-yl,6-azaspiro[2.5]oct-6-yl, octahydro-2H-isoindol-2-yl,3-azaspiro[5.5]undec-3-yl, 1,3-dihydro-2H-isoindol-2-yl, or1,4-dioxa-8-azaspiro[4.5]dec-8-yl. In further subgroups of compounds Dis

wherein g is 0, 1, or 2; R_(M) is each independently fluoro, chloro,methyl, methoxy, trifluoromethyl, or trifluoromethoxy; and

is as defined above. In further subgroups of compounds D is

wherein R_(M1) is each independently hydrogen, fluoro, chloro, or methyland

is as defined above (e.g., 3-azabicyclo[3.2.0]hept-3-yl,octahydro-2H-isoindol-2-yl, 2-azabicyclo[2.2.2]oct-2-yl,6-azaspiro[2.5]oct-6-yl, 3-azaspiro[5.5]undec-3-yl,1,3-dihydro-2H-isoindol-2-yl, 1,4-dioxa-8-azaspiro[4.5]dec-8-yl).

In other groups of compounds according Formula I_(F) and the foregoingembodiments and description of this aspect of the invention, D is

wherein

is a monocyclic 4-8 membered nitrogen-containing heterocycle (e.g.,azetidinyl, pyrrolidinyl, piperidinyl) substituted with one or moreR_(G2), wherein R_(G2) at each occurrence is each independently halogen,—C(O)C₁-C₆alkyl, —C₁-C₆alkyl, —C₁-C₆haloalkyl, —O—C₁-C₆alkyl, or—O—C₁-C₆haloalkyl; and R_(M) is each independently halogen, —C₁-C₆alkyl,—C₁-C₆haloalkyl, —O—C₁-C₆alkyl, or —O—C₁-C₆haloalkyl. In each group ofcompounds according to the foregoing embodiments

is azetidinyl, pyrrolidinyl, or piperidinyl substituted with one or twoR_(G2), wherein R_(G2) at each occurrence is each methyl, ethyl,isopropyl, tert-butyl, fluoro, chloro, or trifluoromethyl; and R_(M) iseach independently fluoro, chloro, or methyl. For example

is 4,4-dimethylpiperidin-1-yl, 4,4-difluoropiperidin-1-yl,2,6-dimethylpiperidin-1-yl, 4-(propan-2-yl)piperidin-1-yl,4-fluoropiperidin-1-yl, 3,5-dimethylpiperidin-1-yl,4-(trifluoromethyl)piperidin-1-yl, 4-methylpiperidin-1-yl,4-tert-butylpiperidin-1-yl, 2-oxopiperidin-1-yl, or3,3-dimethylazetidin-1-yl.

In still another aspect, the present invention features compounds ofFormula I_(G) and pharmaceutically acceptable salts thereof,

wherein:

-   -   X is

wherein X is optionally substituted with one or more R_(A)

-   -   A is

wherein A is optionally substituted with one or more R_(A);

-   -   B is

wherein B is optionally substituted with one or more R_(A); and

-   -   Y, Z, R_(A), and D are as described hereinabove (e.g., as        described for Formula I, I_(A), I_(B), I_(C), I_(D), I_(E) or        I_(F), preferably as described for Formula I_(E)).

In one embodiment, this aspect of the invention features compounds ofFormula I_(G) and pharmaceutically acceptable salts thereof, wherein: Xis

wherein A is optionally substituted with one R_(A); B is

wherein B is optionally substituted with one R_(A); R_(A) is halogen(e.g., fluoro, chloro); L_(S)-R_(E) where L_(S) is a single bond andR_(E) is —C₁-C₆alkyl (e.g., methyl), —O—R_(S) (e.g., —O—C₁-C₆alkyl,—OCH₃), or —C₁-C₆alkyl optionally substituted with one or more halogen(e.g., —CF₃); or L_(S)-R_(E) where L_(S) is a C₁-C₆alkylene and R_(E) is—O—R_(S) (e.g., —C₁-C₆alkyl-O—C₁-C₆alkyl, —CH₂OCH₃); Y and Z are eachindependently

T—R_(D) is each independently

and D is as defined hereinabove.

In another embodiment, this aspect of the invention features compoundsof Formula I_(G) and pharmaceutically acceptable salts thereof, whereinX is

A is

wherein A is optionally substituted with one R_(A); B is

wherein B is optionally substituted with one R_(A); R_(A) is halogen(e.g., fluoro, chloro); L_(S)-R_(E) where L_(S) is a single bond andR_(E) is —C₁-C₆alkyl (e.g., methyl), —O—R_(S) (e.g., —O—C₁-C₆alkyl,—OCH₃), or —C₁-C₆alkyl optionally substituted with one or more halogen(e.g., —CF₃); or L_(S)-R_(E) where L_(S) is a C₁-C₆alkylene and R_(E) is—O—R_(S) (e.g., —C₁-C₆alkyl-O—C₁-C₆alkyl, —CH₂OCH₃); Y and Z are eachindependently

T—R_(D) is each independently

wherein compounds having (S) stereochemistry (e.g.,

are particularly contemplated; and D is as defined hereinabove. Thissubgroup includes compounds where A and B are both substituted by oneR_(A); compounds where A and B are both substituted by zero R_(A);compounds where A is substituted by one R_(A) and B is substituted byzero R_(A); and compounds where A is substituted by zero R_(A) and B issubstituted by one R_(A). In particular, according to this subgroup areincluded compounds where A is

and B is

or A is

and B is

or A is

and B is

or A is

and B is

According to each of the foregoing embodiments and description of thisaspect of the invention of Formula I_(G) are groups and subgroups ofcompounds having particular values for D. Included in each of theforegoing embodiments are groups and subgroups of compounds with thefollowing particular values for D:

Groups of compounds according to this aspect of the invention includecompounds where D is C₆-C₁₀aryl (e.g., phenyl, naphthyl, indanyl), or 5-to 10-membered heteroaryl (pyridinyl, thiazolyl,4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, indazolyl,benzo[d][1,3]dioxol-5-yl), and D is substituted with one or more R_(M).Particular subgroups according to this aspect and these embodimentsinclude compounds wherein R_(M) is halogen (e.g., fluoro, chloro,bromo); C₁-C₆alkyl (e.g., tert-butyl); C₁-C₆alkyl substituted with oneor more halogen (e.g., CF₃); —O—C₁-C₆alkyl (e.g., —O—CH₂CH₃);—O—C₁-C₆alkyl substituted at each occurrence with one or more halogen(e.g., —O—CF₃, —O—CH₂CHF₂) or —O—C₁-C₆alkyl (—O—CH₂CH₂OCH₃);—O—C₁-C₆alkyl (e.g., —O—CH₂) substituted with an optionally substituted3- to 12-membered heterocycle (e.g., 3-ethyloxetan-3-yl,1,3-dioxolan-4-yl); —O—R_(S) where R_(S) is an optionally substituted 3-to 12-membered carbocycle or heterocycle (e.g., cyclopentyl, cyclohexyl,phenyl, 1,3-dioxan-5-yl); —N(R_(S))C(O)R_(S)′ wherein R_(S) and R_(S)′are each independently C₁-C₆alkyl (e.g., —N(t-Bu)C(O)Me); SF₅; —SO₂R_(S)wherein R_(S) is C₁-C₆alkyl (e.g., —SO₂Me); or C₃-C₁₂carbocycle (e.g.,cyclopropyl, cyclohexyl, phenyl). Other subgroups according to thisembodiment include compounds wherein D is phenyl substituted by G₂ andoptionally substituted by one or more R_(M), wherein G₂ is a 3- to12-membered heterocycle (e.g., pyridinyl, piperidinyl, pyrrolidinyl,azetidinyl, oxazolyl) wherein the heterocycle is optionally substitutedwith one or more substituents selected from halogen, hydroxy, oxo,cyano, C₁-C₆alkyl (e.g., methyl), C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆haloalkyl (e.g., CF₃), C₂-C₆haloalkenyl, C₂-C₆haloalkynyl,—O—C₁-C₆alkyl (e.g., —O—CH₃), —C(O)OR_(S) (e.g., —C(O)OCH₃), —C(O)R₅(e.g., —C(O)CH₃), —N(R_(S)R_(S)′), or L₄-G₃; R_(M) is halogen (e.g.,fluoro, chloro), alkyl (e.g., methyl), haloalkyl (e.g., CF₃), or—O—C₁-C₆alkyl (e.g., —O—CH₃); and L₄, G₃, R_(S), and R_(S)′ are asdefined hereinabove.

In certain groups of compounds according to Formula I_(G) and theforegoing embodiments and description of this aspect of the invention, Dis

where R_(M) is fluoro, chloro, tert-butyl, —O—CH₂CH₃, —O—CF₃,—O—CH₂CHF₂, —O—CH₂CH₂OCH₃, —O—CH₂-(3-ethyloxetan-3-yl),—O—CH₂-(1,3-dioxolan-4-yl), —O-cyclopentyl, —O-cyclohexyl, —O-phenyl,—O-(1,3-dioxan-5-yl), cyclopropyl, cyclohexyl, phenyl, SF₅, —SO₂Me, or—N(t-Bu)C(O)Me and D is optionally substituted by one or more additionalR_(M), selected from the group consisting of halogen (e.g., fluoro,chloro) or C₁-C₆alkyl (e.g., methyl).

In other groups of compounds according Formula I_(G) and the foregoingembodiments and description of this aspect of the invention, D is

wherein O₂ is pyridinyl (e.g., pyridin-2-yl), piperidin-1-yl,4,4-dimethylpiperidin-1-yl, 4,4-difluoropiperidin-1-yl,2,6-dimethylpiperidin-1-yl, 4-(propan-2-yl)piperidin-1-yl,4-fluoropiperidin-1-yl, 3,5-dimethylpiperidin-1-yl,4-(trifluoromethyl)piperidin-1-yl, 4-methylpiperidin-1-yl,4-tert-butylpiperidin-1-yl, 2-oxopiperidin-1-yl,3,3-dimethylazetidin-1-yl, or oxazolyl (e.g., 1,3-oxazol-2-yl) and D isoptionally substituted by one or more additional R_(M) selected from thegroup consisting of halogen (e.g., fluoro, chloro), or C_(r) C₆alkyl(e.g., methyl). In particular according to these groups are compoundswhere D is

G₂ is piperidin-1-yl, 4,4-dimethylpiperidin-1-yl,4,4-difluoropiperidin-1-yl, 2,6-dimethylpiperidin-1-yl,4-(propan-2-yl)piperidin-1-yl, 4-fluoropiperidin-1-yl,3,5-dimethylpiperidin-1-yl, 4-(trifluoromethyl)piperidin-1-yl,4-methylpiperidin-1-yl, 4-tert-butylpiperidin-1-yl, 2-oxopiperidin-1-yl,or 3,3-dimethylazetidin-1-yl; and R_(M1) is each independently hydrogen,fluoro, chloro, or methyl.

In other groups of compounds according Formula I_(G) and the foregoingembodiments and description of this aspect of the invention, D is

wherein G₁ is N, C—H, or C—R_(M); G2 is

wherein

R_(M), and g are as defined hereinabove. In particular according tothese groups, R_(M) is each independently fluoro, chloro, methyl,methoxy, trifluoromethyl, or trifluoromethoxy; g is 0, 1, or 2; and

is as defined hereinabove. In further subgroups L₄ is a bond; G₂ is

R_(M) is each independently fluoro, chloro, methyl, methoxy,trifluoromethyl, or trifluoromethoxy; and g is 0, 1, or 2. In particularsubgroups,

is 3-phenylazetidin-1-yl, 3-phenylpyrrolidin-1-yl,4-phenylpiperazin-1-yl, 4-phenylpiperidin-1-yl,4-phenyl-3,6-dihydropyridin-1(2H)-yl, 4,4-diphenylpiperidin-1-yl,4-acetyl-4-phenylpiperidin-1-yl, 4-(4-methoxyphenyl)piperidin-1-yl,4-(4-fluorophenyl)piperidin-1-yl, or 3-phenylpiperidin-1-yl; R_(M) iseach independently fluoro, chloro, methyl, methoxy, trifluoromethyl, ortrifluoromethoxy; and g is 0, 1, or 2. In other subgroups L4 is C₁-C₆alkylene, —O—, or —S(O)₂—; G₂ is

R_(M) is each independently fluoro, chloro, methyl, methoxy,trifluoromethyl, or trifluoromethoxy; and g is 0, 1, or 2. In particularsubgroups,

is 4-tosylpiperazin-1-yl, 4-phenoxypiperidin-1-yl,3-phenoxypyrrolidin-1-yl, 4-benzylpiperidin-1-yl,4-phenethylpiperidin-1-yl, or 3-phenylpropyl)piperidin-1-yl; R_(M) iseach independently fluoro, chloro, methyl, methoxy, trifluoromethyl, ortrifluoromethoxy; and g is 0, 1, or 2. In further subgroups of compoundsD is

wherein G₃ is phenyl optionally substituted with one or two R_(G3); g is0, 1, or 2; R_(M) is each independently fluoro, chloro, methyl, methoxy,trifluoromethyl, or trifluoromethoxy; and

R_(G3) are as defined above. In other groups of compounds D is

wherein L₄ is C₁-C₆ alkylene, —O—, or —S(O)₂—; G₃ is phenyl optionallysubstituted with one or two R_(G3); g is 0, 1, or 2; R_(M) is eachindependently fluoro, chloro, methyl, methoxy, trifluoromethyl, ortrifluoromethoxy; and

R_(G3) are as defined above. In further subgroups of compounds D is

wherein G₃ is phenyl optionally substituted with one or two R_(G3) asdefined hereinabove; R_(M1) is each independently hydrogen, fluoro,chloro, or methyl; and R_(G2) is an optional substituent, as describedabove, selected from the group consisting of —C(O)C₁-C₆alkyl,—C₁-C₆alkyl, —C₁-C₆haloalkyl, —O—C₁-C₆alkyl, and —O—C₁-C₆haloalkyl.

In other groups of compounds according Formula I_(G) and the foregoingembodiments and description of this aspect of the invention, D is

wherein G₁ is N, C—H, or C—R_(M); G₂ is

wherein

R_(M), and g are as defined hereinabove. In particular according tothese subgroups, R_(M) is each independently fluoro, chloro, methyl,methoxy, trifluoromethyl, or trifluoromethoxy; g is 0, 1, or 2; and

is 3-azabicyclo[3.2.0]hept-3-yl, 2-azabicyclo[2.2.2]oct-2-yl,6-azaspiro[2.5]oct-6-yl, octahydro-2H-isoindol-2-yl,3-azaspiro[5.5]undec-3-yl, 1,3-dihydro-2H-isoindol-2-yl, or1,4-dioxa-8-azaspiro[4.5]dec-8-yl. In further subgroups of compounds Dis

wherein g is 0, 1, or 2; R_(M) is each independently fluoro, chloro,methyl, methoxy, trifluoromethyl, or trifluoromethoxy; and

is as defined above. In further subgroups of compounds D is

wherein R_(M1) is each independently hydrogen, fluoro, chloro, or methyland

is as defined above (e.g., 3-azabicyclo[3.2.0]hept-3-yl,octahydro-2H-isoindol-2-yl, 2-azabicyclo[2.2.2]oct-2-yl,6-azaspiro[2.5]oct-6-yl, 3-azaspiro[5.5]undec-3-yl,1,3-dihydro-2H-isoindol-2-yl, 1,4-dioxa-8-azaspiro[4.5]dec-8-yl).

In other groups of compounds according Formula I_(G) and the foregoingembodiments and description of this aspect of the invention, D is

wherein

is a monocyclic 4-8 membered nitrogen-containing heterocycle (e.g.,azetidinyl, pyrrolidinyl, piperidinyl) substituted with one or moreR_(G2), wherein R_(G2) at each occurrence is each independently halogen,—C(O)C₁-C₆alkyl, —C₁-C₆alkyl, —C₁-C₆haloalkyl, —O—C₁-C₆alkyl, or—O—C₁-C₆haloalkyl; and R_(M) is each independently halogen, —C₁-C₆alkyl,—C₁-C₆haloalkyl, —O—C₁-C₆alkyl, or —O—C₁-C₆haloalkyl. In each group ofcompounds according to the foregoing embodiments

is azetidinyl, pyrrolidinyl, or piperidinyl substituted with one or twoR_(G2), wherein R_(G2) at each occurrence is each methyl, ethyl,isopropyl, tert-butyl, fluoro, chloro, or trifluoromethyl; and R_(M) iseach independently fluoro, chloro, or methyl. For example

is 4,4-dimethylpiperidin-1-yl, 4,4-difluoropiperidin-1-yl,2,6-dimethylpiperidin-1-yl, 4-(propan-2-yl)piperidin-1-yl,4-fluoropiperidin-1-yl, 3,5-dimethylpiperidin-1-yl,4-(trifluoromethyl)piperidin-1-yl, 4-methylpiperidin-1-yl,4-tert-butylpiperidin-1-yl, 2-oxopiperidin-1-yl, or3,3-dimethylazetidin-1-yl.

The present invention also features compounds of Formulae I_(E), I_(F)and I_(G) as described herein (including each embodiment describedhereunder) and pharmaceutically acceptable salts thereof, wherein:

-   -   R_(E) is independently selected at each occurrence from        —O—R_(S), —S—R_(S), —C(O)R_(S), —OC(O)R_(S), —C(O)OR_(S),        —N(R_(S)R_(S)′), —S(O)R_(S), —SO₂R_(S), —C(O)N(R_(S)R_(S)′),        —N(R_(S))C(O)R_(S)′, —N(R_(S))C(O)N(R_(S)′R_(S)″),        —N(R_(S))SO₂R_(S)′, —SO₂N(R_(S)R_(S)′),        —N(R_(S))SO₂N(R_(S)′R_(S)″), —N(R_(S))S(O)N(R_(S)′R_(S)″),        —OS(O)—R_(S), —OS(O)₂—R_(S), —S(O)₂OR_(S), —S(O)OR_(S),        —OC(O)OR_(S), —N(R_(S))C(O)OR_(S)′, —OC(O)N(R_(S)R_(S)′),        —N(R_(S))S(O)—R_(S)′, —S(O)N(R_(S)R_(S)′), —P(O)(OR_(S))₂,        ═C(R_(S)R_(S)′), or —C(O)N(R_(S))C(O)—R_(S)′; or C₁-C₆alkyl,        C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is independently        optionally substituted at each occurrence with one or more        substituents selected from halogen, hydroxy, mercapto, amino,        carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or        cyano; or C₃-C₁₂carbocycle or 3- to 12-membered heterocycle,        each of which is independently optionally substituted at each        occurrence with one or more substituents selected from halogen,        hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy,        phosphono, thioxo, formyl, cyano, trimethylsilyl, C₁-C₆alkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl, C₂-C₆haloalkenyl,        C₂-C₆haloalkynyl, —O—R_(S), —S—R_(S), —C(O)R_(S), —C(O)OR_(S),        or —N(R_(S)R_(S)′).

The compounds of the present invention can be used in the form of salts.Depending on the particular compound, a salt of a compound may beadvantageous due to one or more of the salt's physical properties, suchas enhanced pharmaceutical stability under certain conditions or desiredsolubility in water or oil. In some instances, a salt of a compound maybe useful for the isolation or purification of the compound.

Where a salt is intended to be administered to a patient, the saltpreferably is pharmaceutically acceptable. Pharmaceutically acceptablesalts include, but are not limited to, acid addition salts, baseaddition salts, and alkali metal salts.

Pharmaceutically acceptable acid addition salts may be prepared frominorganic or organic acids. Examples of suitable inorganic acidsinclude, but are not limited to, hydrochloric, hydrobromic, hydroiodic,nitric, carbonic, sulfuric, and phosphoric acid. Examples of suitableorganic acids include, but are not limited to, aliphatic,cycloaliphatic, aromatic, araliphatic, heterocyclyl, carboxylic, andsulfonic classes of organic acids. Specific examples of suitable organicacids include acetate, trifluoroacetate, formate, propionate, succinate,glycolate, gluconate, digluconate, lactate, malate, tartaric acid,citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate,glutamate, benzoate, anthranilic acid, mesylate, stearate, salicylate,p-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate),methanesulfonate, ethanesulfonate, benzenesulfonate, pantothenate,toluenesulfonate, 2-hydroxyethanesulfonate, sufanilate,cyclohexylaminosulfonate, algenic acid, b-hydroxybutyric acid,galactarate, galacturonate, adipate, alginate, bisulfate, butyrate,camphorate, camphorsulfonate, cyclopentanepropionate, dodecylsulfate,glycoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate,nicotinate, 2-naphthalesulfonate, oxalate, palmoate, pectinate,persulfate, 3-phenylpropionate, picrate, pivalate, thiocyanate,tosylate, and undecanoate.

Pharmaceutically acceptable base addition salts include, but are notlimited to, metallic salts and organic salts. Non-limiting examples ofsuitable metallic salts include alkali metal (group Ia) salts, alkalineearth metal (group IIa) salts, and other pharmaceutically acceptablemetal salts. Such salts may be made, without limitation, from aluminum,calcium, lithium, magnesium, potassium, sodium, or zinc. Non-limitingexamples of suitable organic salts can be made from tertiary amines andquaternary amine, such as tromethamine, diethylamine,N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine (N-methylglucamine), and procaine. Basicnitrogen-containing groups can be quaternized with agents such as alkylhalides (e.g., methyl, ethyl, propyl, butyl, decyl, lauryl, myristyl,and stearyl chlorides/bromides/iodides), dialkyl sulfates (e.g.,dimethyl, diethyl, dibutyl, and diamyl sulfates), aralkyl halides (e.g.,benzyl and phenethyl bromides), and others.

The compounds or salts of the present invention may exist in the form ofsolvates, such as with water (i.e., hydrates), or with organic solvents(e.g., with methanol, ethanol or acetonitrile to form, respectively,methanolate, ethanolate or acetonitrilate).

The compounds or salts of the present invention may also be used in theform of prodrugs. Some prodrugs are aliphatic or aromatic esters derivedfrom acidic groups on the compounds of the invention. Others arealiphatic or aromatic esters of hydroxyl or amino groups on thecompounds of the invention. Phosphate prodrugs of hydroxyl groups arepreferred prodrugs.

The compounds of the invention may comprise asymmetrically substitutedcarbon atoms known as chiral centers. These compounds may exist, withoutlimitation, as single stereoisomers (e.g., single enantiomers or singlediastereomer), mixtures of stereoisomers (e.g. a mixture of enantiomersor diastereomers), or racemic mixtures. Compounds identified herein assingle stereoisomers are meant to describe compounds that are present ina form that is substantially free from other stereoisomers (e.g.,substantially free from other enantiomers or diastereomers). By“substantially free,” it means that at least 80% of the compound in acomposition is the described stereoisomer; preferably, at least 90% ofthe compound in a composition is the described stereoisomer; and morepreferably, at least 95%, 96%, 97%, 98% or 99% of the compound in acomposition is the described stereoisomer. Where the stereochemistry ofa chiral carbon is not specified in the chemical structure of acompound, the chemical structure is intended to encompass compoundscontaining either stereoisomer of the chiral center.

Individual stereoisomers of the compounds of this invention can beprepared using a variety of methods known in the art. These methodsinclude, but are not limited to, stereospecific synthesis,chromatographic separation of diastereomers, chromatographic resolutionof enantiomers, conversion of enantiomers in an enantiomeric mixture todiastereomers followed by chromatographically separation of thediastereomers and regeneration of the individual enantiomers, andenzymatic resolution.

Stereospecific synthesis typically involves the use of appropriateoptically pure (enantiomerically pure) or substantial optically purematerials and synthetic reactions that do not cause racemization orinversion of stereochemistry at the chiral centers. Mixtures ofstereoisomers of compounds, including racemic mixtures, resulting from asynthetic reaction may be separated, for example, by chromatographictechniques as appreciated by those of ordinary skill in the art.Chromatographic resolution of enantiomers can be accomplished by usingchiral chromatography resins, many of which are commercially available.In a non-limiting example, racemate is placed in solution and loadedonto the column containing a chiral stationary phase. Enantiomers canthen be separated by HPLC.

Resolution of enantiomers can also be accomplished by convertingenantiomers in a mixture to diastereomers by reaction with chiralauxiliaries. The resulting diastereomers can be separated by columnchromatography or crystallization/re-crystallization. This technique isuseful when the compounds to be separated contain a carboxyl, amino orhydroxyl group that will form a salt or covalent bond with the chiralauxiliary. Non-limiting examples of suitable chiral auxiliaries includechirally pure amino acids, organic carboxylic acids or organosulfonicacids. Once the diastereomers are separated by chromatography, theindividual enantiomers can be regenerated. Frequently, the chiralauxiliary can be recovered and used again.

Enzymes, such as esterases, phosphatases or lipases, can be useful forthe resolution of derivatives of enantiomers in an enantiomeric mixture.For example, an ester derivative of a carboxyl group in the compounds tobe separated can be treated with an enzyme which selectively hydrolyzesonly one of the enantiomers in the mixture. The resultingenantiomerically pure acid can then be separated from the unhydrolyzedester.

Alternatively, salts of enantiomers in a mixture can be prepared usingany suitable method known in the art, including treatment of thecarboxylic acid with a suitable optically pure base such as alkaloids orphenethylamine, followed by precipitation orcrystallization/re-crystallization of the enantiomerically pure salts.Methods suitable for the resolution/separation of a mixture ofstereoisomers, including racemic mixtures, can be found in ENANTIOMERS,RACEMATES, AND RESOLUTIONS (Jacques et al., 1981, John Wiley and Sons,New York, N.Y.).

A compound of this invention may possess one or more unsaturatedcarbon-carbon double bonds. All double bond isomers, such as the cis (Z)and trans (E) isomers, and mixtures thereof are intended to beencompassed within the scope of a recited compound unless otherwisespecified. In addition, where a compound exists in various tautomericforms, a recited compound is not limited to any one specific tautomer,but rather is intended to encompass all tautomeric forms.

Certain compounds of the invention may exist in different stableconformational forms which may be separable. Torsional asymmetry due torestricted rotations about an asymmetric single bond, for examplebecause of steric hindrance or ring strain, may permit separation ofdifferent conformers. The invention encompasses each conformationalisomer of these compounds and mixtures thereof.

Certain compounds of the invention may also exist in zwitterionic formand the invention encompasses each zwitterionic form of these compoundsand mixtures thereof.

The compounds of the present invention are generally described hereinusing standard nomenclature. For a recited compound having asymmetriccenter(s), it should be understood that all of the stereoisomers of thecompound and mixtures thereof are encompassed in the present inventionunless otherwise specified. Non-limiting examples of stereoisomersinclude enantiomers, diastereomers, and cis-transisomers. Where arecited compound exists in various tautomeric forms, the compound isintended to encompass all tautomeric forms. Certain compounds aredescribed herein using general formulas that include variables (e.g., A,B, D, X, L₁, L₂, L₃, Y, Z, T, R_(A) or R_(B)). Unless otherwisespecified, each variable within such a formula is defined independentlyof any other variable, and any variable that occurs more than one timein a formula is defined independently at each occurrence. If moietiesare described as being “independently” selected from a group, eachmoiety is selected independently from the other. Each moiety thereforecan be identical to or different from the other moiety or moieties.

The number of carbon atoms in a hydrocarbyl moiety can be indicated bythe prefix “C_(x)—C_(y),” where x is the minimum and y is the maximumnumber of carbon atoms in the moiety. Thus, for example, “C₁-C₆alkyl”refers to an alkyl substituent containing from 1 to 6 carbon atoms.Illustrating further, C₃-C₆cycloalkyl means a saturated hydrocarbyl ringcontaining from 3 to 6 carbon ring atoms. A prefix attached to amultiple-component substituent only applies to the first component thatimmediately follows the prefix. To illustrate, the term“carbocyclylalkyl” contains two components: carbocyclyl and alkyl. Thus,for example, C₃-C₆carbocyclylC₁-C₆alkyl refers to a C₃-C₆carbocyclylappended to the parent molecular moiety through a C₁-C₆alkyl group.

Unless otherwise specified, when a linking element links two otherelements in a depicted chemical structure, the leftmost-describedcomponent of the linking element is bound to the left element in thedepicted structure, and the rightmost-described component of the linkingelement is bound to the right element in the depicted structure. Toillustrate, if the chemical structure is -L_(S)-M-L_(S)′— and M is—N(R_(B))S(O)—, then the chemical structure is-L_(S)-N(R_(B))S(O)-L_(S)′-.

If a linking element in a depicted structure is a bond, then the elementleft to the linking element is joined directly to the element right tothe linking element via a covalent bond. For example, if a chemicalstructure is depicted as -L_(S)-M-L_(S)′- and M is selected as bond,then the chemical structure will be -L_(S)-L_(S)′-. If two or moreadjacent linking elements in a depicted structure are bonds, then theelement left to these linking elements is joined directly to the elementright to these linking elements via a covalent bond. For instance, if achemical structure is depicted as -L_(S)-M-L_(S)′-M′-L_(S)″—, and M andL_(S)′ are selected as bonds, then the chemical structure will be-L_(S)-M′— L_(S)″—. Likewise, if a chemical structure is depicted as-L_(S)-M-L_(S)′-M′-L_(S)″—, and M, L_(S)′ and M′ are bonds, then thechemical structure will be -L_(S)-L_(S)″—.

When a chemical formula is used to describe a moiety, the dash(s)indicates the portion of the moiety that has the free valence(s).

If a moiety is described as being “optionally substituted”, the moietymay be either substituted or unsubstituted. If a moiety is described asbeing optionally substituted with up to a particular number ofnon-hydrogen radicals, that moiety may be either unsubstituted, orsubstituted by up to that particular number of non-hydrogen radicals orby up to the maximum number of substitutable positions on the moiety,whichever is less. Thus, for example, if a moiety is described as aheterocycle optionally substituted with up to three non-hydrogenradicals, then any heterocycle with less than three substitutablepositions will be optionally substituted by up to only as manynon-hydrogen radicals as the heterocycle has substitutable positions. Toillustrate, tetrazolyl (which has only one substitutable position) willbe optionally substituted with up to one non-hydrogen radical. Toillustrate further, if an amino nitrogen is described as beingoptionally substituted with up to two non-hydrogen radicals, then aprimary amino nitrogen will be optionally substituted with up to twonon-hydrogen radicals, whereas a secondary amino nitrogen will beoptionally substituted with up to only one non-hydrogen radical.

Where a moiety is substituted with oxo or thioxo, it means that themoiety contains a carbon atom covalently bonded to at least twohydrogens (e.g., CH₂), and the two hydrogen radicals are substitutedwith oxo or thioxo to form C═O or C═S, respectively.

The term “alkenyl” means a straight or branched hydrocarbyl chaincontaining one or more double bonds. Each carbon-carbon double bond mayhave either cis or trans geometry within the alkenyl moiety, relative togroups substituted on the double bond carbons. Non-limiting examples ofalkenyl groups include ethenyl(vinyl), 2-propenyl, 3-propenyl,1,4-pentadienyl, 1,4-butadienyl, 1-butenyl, 2-butenyl, and 3-butenyl.

The term “alkenylene” refers to a divalent unsaturated hydrocarbyl chainwhich may be linear or branched and which has at least one carbon-carbondouble bond. Non-limiting examples of alkenylene groups include—C(H)═C(H)—, —C(H)═C(H)—CH₂—, —C(H)═C(H)—CH₂—CH₂—, —CH₂—C(H)═C(H)—CH₂—,—C(H)═C(H)—CH(CH₃)—, and —CH₂—C(H)═C(H)—CH(CH₂CH₃)—.

The term “alkyl” means a straight or branched saturated hydrocarbylchain. Non-limiting examples of alkyl groups include methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl,iso-amyl, and hexyl.

The term “alkylene” denotes a divalent saturated hydrocarbyl chain whichmay be linear or branched. Representative examples of alkylene include,but are not limited to, —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—,and —CH₂CH(CH₃)CH₂—.

The term “alkynyl” means a straight or branched hydrocarbyl chaincontaining one or more triple bonds. Non-limiting examples of alkynylinclude ethynyl, 1-propynyl, 2-propynyl, 3-propynyl, decynyl, 1-butynyl,2-butynyl, and 3-butynyl.

The term “alkynylene” refers to a divalent unsaturated hydrocarbon groupwhich may be linear or branched and which has at least one carbon-carbontriple bonds. Representative alkynylene groups include, by way ofexample, —C≡C—, —C≡—CH₂—, —C≡C—CH₂—CH₂—, —CH₂—C≡C—CH₂—, —C≡C—CH(CH₃)—,and —CH₂—C≡C—CH(CH₂CH₃)—.

The term “carbocycle” or “carbocyclic” or “carbocyclyl” refers to asaturated (e.g., “cycloalkyl”), partially saturated (e.g.,“cycloalkenyl” or “cycloalkynyl”) or completely unsaturated (e.g.,“aryl”) ring system containing zero heteroatom ring atom. “Ring atoms”or “ring members” are the atoms bound together to form the ring orrings. A carbocyclyl may be, without limitation, a single ring, twofused rings, or bridged or spiro rings. A substituted carbocyclyl mayhave either cis or trans geometry. Representative examples ofcarbocyclyl groups include, but are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,cyclopentenyl, cyclopentadienyl, cyclohexadienyl, adamantyl,decahydro-naphthalenyl, octahydro-indenyl, cyclohexenyl, phenyl,naphthyl, indanyl, 1,2,3,4-tetrahydro-naphthyl, indenyl, isoindenyl,decalinyl, and norpinanyl. A carbocycle group can be attached to theparent molecular moiety through any substitutable carbon ring atom.Where a carbocycle group is a divalent moiety linking two other elementsin a depicted chemical structure (such as A in Formula I), thecarbocycle group can be attached to the two other elements through anytwo substitutable ring atoms. Likewise, where a carbocycle group is atrivalent moiety linking three other elements in a depicted chemicalstructure (such as X in Formula I), the carbocycle group can be attachedto the three other elements through any three substitutable ring atoms,respectively.

The term “carbocyclylalkyl” refers to a carbocyclyl group appended tothe parent molecular moiety through an alkylene group. For instance,C₃-C₆carbocyclylC₁-C₆alkyl refers to a C₃-C₆carbocyclyl group appendedto the parent molecular moiety through C₁-C₆alkylene.

The term “cycloalkenyl” refers to a non-aromatic, partially unsaturatedcarbocyclyl moiety having zero heteroatom ring member. Representativeexamples of cycloalkenyl groups include, but are not limited to,cyclobutenyl, cyclopentenyl, cyclohexenyl, and octahydronaphthalenyl.

The term “cycloalkyl” refers to a saturated carbocyclyl group containingzero heteroatom ring member. Non-limiting examples of cycloalkylsinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, decalinyl and norpinanyl.

The prefix “halo” indicates that the substituent to which the prefix isattached is substituted with one or more independently selected halogenradicals. For example, “C₁-C₆haloalkyl” means a C₁-C₆alkyl substituentwherein one or more hydrogen atoms are replaced with independentlyselected halogen radicals. Non-limiting examples of C₁-C₆haloalkylinclude chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl,trifluoromethyl, and 1,1,1-trifluoroethyl. It should be recognized thatif a substituent is substituted by more than one halogen radical, thosehalogen radicals may be identical or different (unless otherwisestated).

The term “heterocycle” or “heterocyclo” or “heterocyclyl” refers to asaturated (e.g., “heterocycloalkyl”), partially unsaturated (e.g.,“heterocycloalkenyl” or “heterocycloalkynyl”) or completely unsaturated(e.g., “heteroaryl”) ring system where at least one of the ring atoms isa heteroatom (i.e., nitrogen, oxygen or sulfur), with the remaining ringatoms being independently selected from the group consisting of carbon,nitrogen, oxygen and sulfur. A heterocycle may be, without limitation, asingle ring, two fused rings, or bridged or spiro rings. A heterocyclegroup can be linked to the parent molecular moiety via any substitutablecarbon or nitrogen atom(s) in the group. Where a heterocycle group is adivalent moiety that links two other elements in a depicted chemicalstructure (such as A in Formula I), the heterocycle group can beattached to the two other elements through any two substitutable ringatoms. Likewise, where a heterocycle group is a trivalent moiety thatlinks three other elements in a depicted chemical structure (such as Xin Formula I), the heterocycle group can be attached to the three otherelements through any three substitutable ring atoms, respectively.

A heterocyclyl may be, without limitation, a monocycle which contains asingle ring. Non-limiting examples of monocycles include furanyl,dihydrofuranyl, tetrahydrofuranyl, pyrrolyl, isopyrroyl, pyrrolinyl,pyrrolidinyl, imidazolyl, isoimidazolyl, imidazolinyl, imidazolidinyl,pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, dithiolyl,oxathiolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiazolinyl,isothiazolinyl, thiazolidinyl, isothiazolidinyl, thiadiazolyl,oxathiazolyl, oxadiazolyl (including 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl (also known as “azoximyl”), 1,2,5-oxadiazolyl (alsoknown as “furazanyl”), and 1,3,4-oxadiazolyl), oxatriazolyl (including1,2,3,4-oxatriazolyl and 1,2,3,5-oxatriazolyl), dioxazolyl (including1,2,3-dioxazolyl, 1,2,4-dioxazolyl, 1,3,2-dioxazolyl, and1,3,4-dioxazolyl), oxathiolanyl, pyranyl (including 1,2-pyranyl and1,4-pyranyl), dihydropyranyl, pyridinyl, piperidinyl, diazinyl(including pyridazinyl (also known as “1,2-diazinyl”), pyrimidinyl (alsoknown as “1,3-diazinyl”), and pyrazinyl (also known as “1,4-diazinyl”)),piperazinyl, triazinyl (including s-triazinyl (also known as“1,3,5-triazinyl”), as-triazinyl (also known 1,2,4-triazinyl), andv-triazinyl (also known as 1,2,3-triazinyl), oxazinyl (including1,2,3-oxazinyl, 1,3,2-oxazinyl, 1,3,6-oxazinyl (also known as“pentoxazolyl”), 1,2,6-oxazinyl, and 1,4-oxazinyl), isoxazinyl(including o-isoxazinyl and p-isoxazinyl), oxazolidinyl, isoxazolidinyl,oxathiazinyl (including 1,2,5-oxathiazinyl or 1,2,6-oxathiazinyl),oxadiazinyl (including 1,4,2-oxadiazinyl and 1,3,5,2-oxadiazinyl),morpholinyl, azepinyl, oxepinyl, thiepinyl, thiomorpholinyl, anddiazepinyl.

A heterocyclyl may also be, without limitation, a bicycle containing twofused rings, such as, for example, naphthyridinyl (including[1,8]naphthyridinyl, and [1,6]naphthyridinyl), thiazolpyrimidinyl,thienopyrimidinyl, pyrimidopyrimidinyl, pyridopyrimidinyl,pyrazolopyrimidinyl, indolizinyl, pyrindinyl, pyranopyrrolyl,4H-quinolizinyl, purinyl, pyridopyridinyl (includingpyrido[3,4-b]-pyridinyl, pyrido[3,2-b]-pyridinyl, andpyrido[4,3-b]-pyridinyl), pyridopyrimidine, and pteridinyl. Othernon-limiting examples of fused-ring heterocycles include benzo-fusedheterocyclyls, such as indolyl, isoindolyl, indoleninyl (also known as“pseudoindolyl”), isoindazolyl (also known as “benzpyrazolyl” orindazolyl); benzazinyl (including quinolinyl (also known as“1-benzazinyl”) and isoquinolinyl (also known as “2-benzazinyl”)),benzimidazolyl, phthalazinyl, quinoxalinyl, benzodiazinyl (includingcinnolinyl (also known as “1,2-benzodiazinyl”) and quinazolinyl (alsoknown as “1,3-benzodiazinyl”)), benzopyranyl (including “chromenyl” and“isochromenyl”), benzothiopyranyl (also known as “thiochromenyl”),benzoxazolyl, indoxazinyl (also known as “benzisoxazolyl”), anthranilyl,benzodioxolyl, benzodioxanyl, benzoxadiazolyl, benzofuranyl (also knownas “coumaronyl”), isobenzofuranyl, benzothienyl (also known as“benzothiophenyl”, “thionaphthenyl”, and “benzothiofuranyl”),isobenzothienyl (also known as “isobenzothiophenyl”,“isothionaphthenyl”, and “isobenzothiofuranyl”), benzothiazolyl,4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzothiadiazolyl, benzimidazolyl,benzotriazolyl, benzoxazinyl (including 1,3,2-benzoxazinyl,1,4,2-benzoxazinyl, 2,3,1-benzoxazinyl, and 3,1,4-benzoxazinyl),benzisoxazinyl (including 1,2-benzisoxazinyl and 1,4-benzisoxazinyl),and tetrahydroisoquinolinyl.

A heterocyclyl may also be, without limitation, a spiro ring system,such as, for example, 1,4-dioxa-8-azaspiro[4.5]decanyl.

A heterocyclyl may comprise one or more sulfur atoms as ring members;and in some cases, the sulfur atom(s) is oxidized to SO or SO₂. Thenitrogen heteroatom(s) in a heterocyclyl may or may not be quaternized,and may or may not be oxidized to N-oxide. In addition, the nitrogenheteroatom(s) may or may not be N-protected.

A heterocycle or carbocycle may be further substituted. Unlessspecified, the term “substituted” refers to substitution by independentreplacement of one, two, or three or more of the hydrogen atoms withsubstituents including, but not limited to, —F, —Cl, —Br, —I, hydroxy,protected hydroxy, —NO₂, —N₃, —CN, —NH₂, protected amino, oxo, thioxo,—NH-C₂-C₈-alkenyl, —NH-C₂-C₈-alkynyl, —NH-C₃-C₁₂-cycloalkyl, —NH-aryl,—NH-heteroaryl, —NH-heterocycloalkyl, -dialkylamino, -diarylamino,-diheteroarylamino, —O—C₁-C₁₂-alkyl, —O—C₂-C₈-alkenyl, —O—C₂-C₈-alkynyl,—O—C₃-C₁₂-cycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl,—C(O)—C₁-C₁₂-alkyl, —C(O)—C₂-C₈-alkenyl, —C(O)—C₂-C₈-alkynyl,—C(O)—C₃-C₁₂-cycloalkyl, —C(O)-aryl, —C(O)-heteroaryl,—C(O)-heterocycloalkyl, —CONH₂, —CONH-C₁-C₁₂-alkyl, —CONH-C₂-C₈-alkenyl,—CONH-C₂-C₈-alkynyl, —CONH-C₃-C₁₂-cycloalkyl, —CONH-aryl,—CONH-heteroaryl, —CONH-heterocycloalkyl, —OCO₂—C₁-C₁₂-alkyl,—OCO₂—C₂-C₈-alkenyl, —OCO₂—C₂-C₈-alkynyl, —OCO₂—C₃-C₁₂-cycloalkyl,—OCO₂-aryl, —OCO₂-heteroaryl, —OCO₂-heterocycloalkyl, —OCONH₂,—OCONH-C₁-C₁₂-alkyl, —OCONH-C₂-C₈-alkenyl, —OCONH-C₂-C₈-alkynyl,—OCONH-C₃-C₁₂-cycloalkyl, —OCONH-aryl, —OCONH-heteroaryl,—OCONH-heterocycloalkyl, —NHC(O)—C₁-C₁₂-alkyl, —NHC(O)—C₂-C₈-alkenyl,—NHC(O)—C₂-C₈-alkynyl, —NHC(O)—C₃-C₁₂-cycloalkyl, —NHC(O)-aryl,—NHC(O)-heteroaryl, —NHC(O)-heterocycloalkyl, —NHCO₂—C₁-C₁₂-alkyl,—NHCO₂—C₂-C₈-alkenyl, —NHCO₂—C₂-C₈-alkynyl, —NHCO₂—C₃-C₁₂-cycloalkyl,—NHCO₂-aryl, —NHCO₂-heteroaryl, —NHCO₂-heterocycloalkyl, —NHC(O)NH₂,—NHC(O)NH-C₁-C₁₂-alkyl, —NHC(O)NH-C₂-C₈-alkenyl,—NHC(O)NH-C₂-C₈-alkynyl, C(O)NH—C₃-C₁₂-cycloalkyl, —NHC(O)NH-aryl,—NHC(O)NH-heteroaryl, —NHC(O)NH-heterocycloalkyl, NHC(S)NH₂,—NHC(S)NH-C₁-C₁₂-alkyl, —NHC(S)NH-C₂-C₈-alkenyl,—NHC(S)NH-C₂-C₈-alkynyl, —NHC(S)NH-C₃-C₁₂-cycloalkyl, —NHC(S)NH-aryl,—NHC(S)NH-heteroaryl, —NHC(S)NH-heterocycloalkyl, —NHC(NH)NH₂,—NHC(NH)NH-C₁-C₁₂-alkyl, —NHC(NH)NH-C₂-C₈-alkenyl,—NHC(NH)NH-C₂-C₈-alkynyl, —NHC(NH)NH-C₃-C₁₂-cycloalkyl, —NHC(NH)NH-aryl,—NHC(NH)NH-heteroaryl, —NHC(NH)NH-heterocycloalkyl,—NHC(NH)—C₁-C₁₂-alkyl, —NHC(NH)—C₂-C₈-alkenyl, —NHC(NH)NH-C₂-C₈-alkynyl,—NHC(NH)—C₃-C₁₂-cycloalkyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl,—NHC(NH)-heterocycloalkyl, —C(NH)NH-C₁-C₁₂-alkyl,—C(NH)NH-C₂-C₈-alkenyl, —C(NH)NH-C₂-C₈-alkynyl,—C(NH)NH-C₃-C₁₂-cycloalkyl, —C(NH)NH-aryl, —C(NH)NH-heteroaryl,—C(NH)NH-heterocycloalkyl, —S(O)—C₁-C₁₂-alkyl, —S(O)—C₂-C₈-alkenyl,—S(O)—C₂-C₈-alkynyl, —S(O)—C₃-C₁₂ cycloalkyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)-heterocycloalkyl, —SO₂NH₂, —SO₂NH-C₁-C₁₂-alkyl,—SO₂NH-C₂-C₈-alkenyl, —SO₂NH-C₂-C₈-alkynyl, —SO₂NH-C₃-C₁₂-cycloalkyl,—SO₂NH-aryl, —SO₂NH-heteroaryl, —SO₂NH-heterocycloalkyl,—NHSO₂—C₁-C₁₂-alkyl, —NHSO₂—C₂-C₈-alkenyl, —NHSO₂—C₂-C₈-alkynyl,—NHSO₂—C₃-C₁₂-cycloalkyl, —NHSO₂-aryl, —NHSO₂-heteroaryl,—NHSO₂-heterocycloalkyl, —CH₂NH₂, —CH₂SO₂CH₃, -aryl, -arylalkyl,-heteroaryl, -heteroarylalkyl, -heterocycloalkyl, —C₃-C₁₂-cycloalkyl,polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, —SH,—S—C₁-C₁₂-alkyl, —S-C₂-C₈-alkenyl, —S—C₂-C₈-alkynyl,—S—C₃-C₁₂-cycloalkyl, —S-aryl, -heteroaryl, —S-heterocycloalkyl, ormethylthiomethyl. It is understood that the aryls, heteroaryls, alkyls,and the like can be further substituted.

An “aliphatic” group is a non-aromatic moiety comprised of anycombination of carbon atoms, hydrogen atoms, halogen atoms, oxygen,nitrogen or other atoms, and optionally contains one or more units ofunsaturation, e.g., double and/or triple bonds. Examples of aliphaticgroups are functional groups, such as, 0, OH, NH, NH₂, C(O), S(O)₂,C(O)O, C(O)NH, OC(O)O, OC(O)NH, OC(O)NH₂, S(O)₂NH, S(O)₂NH₂, NHC(O)NH₂,NHC(O)C(O)NH, NHS(O)₂NH, NHS(O)₂NH₂, C(O)NHS(O)₂, C(O)NHS(O)₂NH orC(O)NHS(O)₂NH₂, and the like, groups comprising one or more functionalgroups, non-aromatic hydrocarbons (optionally substituted), and groupswherein one or more carbons of a non-aromatic hydrocarbon (optionallysubstituted) is replaced by a functional group. Carbon atoms of analiphatic group can be optionally oxo-substituted. An aliphatic groupmay be straight chained, branched or cyclic and preferably containsbetween about 1 and about 24 carbon atoms, more typically between about1 and about 12 carbon atoms. In addition to aliphatic hydrocarbongroups, as used herein, aliphatic groups expressly include, for example,alkoxyalkyls, polyalkoxyalkyls, such as polyalkylene glycols,polyamines, and polyimines, for example. Aliphatic groups may beoptionally substituted. A linear aliphatic group is a non-cyclicaliphatic group. It is to be understood that when a linear aliphaticgroup is said to “contain” or “include” or “comprise” one or morespecified functional groups, the linear aliphatic group can be selectedfrom one or more of the specified functional groups or a combinationthereof, or a group wherein one or more carbons of a non-aromatichydrocarbon (optionally substituted) is replaced by a specifiedfunctional group. An exemplary linear aliphatic group is an alkyl,alkenyl or alkynyl, each optionally substituted, which is interrupted orterminated by a functional group.

in a chemical formula refers to a single or double bond.

The term “pharmaceutically acceptable” is used adjectivally to mean thatthe modified noun is appropriate for use as a pharmaceutical product oras a part of a pharmaceutical product.

The term “therapeutically effective amount” refers to the total amountof each active substance that is sufficient to show a meaningful patientbenefit, e.g. a reduction in viral load.

The term “prodrug” refers to derivatives of the compounds of theinvention which have chemically or metabolically cleavable groups andbecome, by solvolysis or under physiological conditions, the compoundsof the invention which are pharmaceutically active in vivo. A prodrug ofa compound may be formed in a conventional manner by reaction of afunctional group of the compound (such as an amino, hydroxy, carboxy orphosphate group). Prodrugs often offer advantages of solubility, tissuecompatibility, or delayed release in mammals (see, Bungard, H., DESIGNOF PRODRUGS, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs includeacid derivatives well known to practitioners of the art, such as, forexample, esters prepared by reaction of the parent acidic compound witha suitable alcohol, or amides prepared by reaction of the parent acidcompound with a suitable amine. Examples of prodrugs include, but arenot limited to, acetate, formate, benzoate or other acylated derivativesof alcohol or amine functional groups within the compounds of theinvention, or phosphate esters of the compounds of the invention.

The term “solvate” refers to the physical association of a compound ofthis invention with one or more solvent molecules, whether organic orinorganic. This physical association often includes hydrogen bonding. Incertain instances the solvate will be capable of isolation, for examplewhen one or more solvent molecules are incorporated in the crystallattice of the crystalline solid. “Solvate” encompasses bothsolution-phase and insoluble solvates. Exemplary solvates include, butare not limited to, hydrates, ethanolates, and methanolates.

The term “N-protecting group” or “N-protected” refers to those groupscapable of protecting an amino group against undesirable reactions.Commonly used N-protecting groups are described in Greene and Wuts,PROTECTING GROUPS IN CHEMICAL SYNTHESIS (3^(rd) ed., John Wiley & Sons,NY (1999). Non-limiting examples of N-protecting groups include acylgroups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl,2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl,phthalyl, o-nitrophenoxyacetyl, benzoyl, 4-chlorobenzoyl,4-bromobenzoyl, or 4-nitrobenzoyl; sulfonyl groups such asbenzenesulfonyl or p-toluenesulfonyl; sulfenyl groups such asphenylsulfenyl (phenyl-S—) or triphenylmethylsulfenyl (trityl-S—);sulfinyl groups such as p-methylphenylsulfinyl (p-methylphenyl-S(O)—) ort-butylsulfinyl (t-Bu-S(O)—); carbamate forming groups such asbenzyloxycarbonyl, p-chlorobenzyloxycarbonyl,p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl,2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl,3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl,2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,2-nitro-4,5-dimethoxybenzyloxycarbonyl,3,4,5-trimethoxybenzyloxycarbonyl,1-(p-biphenylyl)-1-methylethoxycarbonyl,dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl,t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl,ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl,2,2,2-trichloro-ethoxy-carbonyl, phenoxycarbonyl,4-nitro-phenoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl,cyclohexyloxycarbonyl, or phenylthiocarbonyl; alkyl groups such asbenzyl, p-methoxybenzyl, triphenylmethyl, or benzyloxymethyl;p-methoxyphenyl; and silyl groups such as trimethylsilyl. PreferredN-protecting groups include formyl, acetyl, benzoyl, pivaloyl,t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) andbenzyloxycarbonyl (Cbz).

Abbreviations which have been used in the descriptions of the Schemes,Intermediates and Examples that follow are: Ac for acetyl; APCI foratmospheric pressure chemical ionization; aq or aq. for aqueous; atm foratmosphere; Boc for t-butoxycarbonyl; Bu for butyl; t-Bu or tert-butylfor tertiary-butyl; Cbz for benzyloxycarbonyl; dba fordibenzylidineacetone; DCI for desorption chemical ionization; DDQ for2,3-dichloro-5,6-dicyano-p-benzoquinone; DEPBT for3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one; DIBAL fordiisobutylaluminum hydride; DMA for N,N-dimethylacetamide; DME for1,2-dimethoxyethane; DMF for N,N-dimethylformamide; DMSO for dimethylsulfoxide; DMPU for 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone;dppf for 1,1′-bis(diphenylphosphino)ferrocene; EDC, EDAC or EDCI forN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride; e.e. forenantiomeric excess; ELSD for evaporative light scattering detector; ESIfor electrospray ionization; Et for ethyl; Et₃N for triethylamine; EtOAcfor ethyl acetate; EtOH for ethanol; Et₂O for diethyl ether; eq or equivfor equivalents; Fmoc for 9-fluorenylmethoxycarbonyl; HATU forO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate; HOBt for 1-hydroxybenzotriazole; HPLC for highperformance liquid chromatography; HOBt for 1-hydroxybenzotriazole; LCMSfor liquid chromatography/mass spectrometry; mCPBA form-chloroperoxybenzoic acid; Me for methyl; MeOH for methanol; OAc foracetate; Ms for methanesulfonyl; OTF for triflate ortrifluoromethanesulfonate; PDC for pyridinium dichromate; i-Pr forisopropyl; Ph for phenyl; PPh₃ for triphenylphosphine; psi or psig forpounds per square inch (gas); PTFE for polytetrafluoroethylene; PXPd for[(t-Bu)₂PCl]₂PdCl₂, PyBOP for(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate; SEMfor 2-(trimethylsilyl)ethoxymethyl; T3P for propane phosphonic acidanhydride; Tf for trifluorosulfonyl; TFA for trifluoroacetic acid; THFfor tetrahydrofuran; TLC for thin layer chromatography; Troc for2,2,2-trichloroethoxycarbonyl; v/v for volume/volume; wt % for weightpercent; w/v for weight/volume; w/w for weight/weight; XantPhos for4,5-bis(diphenylphosphino)-9,9-dimethylxanthene;

The compounds of the present invention can be prepared using a varietyof methods. As a non-limiting example, the compounds of the presentinvention can be prepared according to Scheme I starting from compoundsof Formula II (e.g., n=0 to 8), Formula V (X₄ can be, for example, O orNR_(A), where R_(A) is as described hereinabove and is preferably H orR_(E) as defined above such as C1-C6alkyl, 3- to 12-membered carbocycleor heterocycle, —C(O)R_(S), —C(O)OR_(S), —C(O)N(R_(S)R_(S)′),—SO₂N(R_(S)R_(S)′), —S(O)₂OR_(S), —S(O)OR_(S), —S(O)N(R_(S)R_(S)′), or asuitable protecting group such as Boc or Fmoc), or Formula VIII (E canbe, for example, 3- to 7-membered carbocycle or heterocycle and isoptionally substituted with one or more R_(A)), wherein A, B, D, Y, Zand R_(A) are as described above. The 1,4-diketones II, V, and VIII canbe reduced to the 1,4-diols using the methods described below, and theresultant racemic, enantiomerically enriched, or meso 1,4-diols may beconverted to the dimesylates III, VI, or IX, or alternatively toditriflates, ditosylates, or dihalides by the methods described below.The dimesylates III, VI, and IX, ditriflates, ditosylates, or dihalidesmay be reacted with an amine, including but not limited to, aniline,3,5-difluoroaniline, 3,4-difluoroaniline, 4-fluoroaniline,3-fluoroaniline, 4-trifluoromethylaniline, 4-chloroaniline, heteroarylamines, alkyl amines, cycloalkyl amines, substituted benzylamines, orallylamine, under the conditions described below to give the compoundsof the invention. L₁ and L₂ can be readily introduced to Formulae II, Vand VIII, as appreciated by those skilled in the art in light of thepresent invention. Likewise, D-L₃-NH₂ can be used instead of D-NH₂, asappreciated by those skilled in the art.

As another non-limiting example, the compounds of the present inventioncan be prepared starting from compounds of Formula II and Formula III asshown in Scheme II. The 1,4-diketones such as Formula IV may be preparedusing known methods (see Nevar, et al., Synthesis:1259-1262 (2000), suchas the reaction of α-bromoketones such as Formula II with methyl ketonessuch as Formula III in the presence of a suitable Lewis acid such asZnCl₂ or Ti(OiPr)₄. For example reaction of II (1 equivalent) with III(1.5 equivalents) in the presence of ZnCl₂ (2 equivalents), diethylamine(1.5 equivalents) and tert-butanol (1.5 equivalents) in a solvent suchas benzene at around room temperature can provide the diketones IV. The1,4-diketones IV may be reduced to the 1,4-diols such as V by the actionof NaBH₄, LiAlH₄, or DIBAL. Alternatively, enantioselective reduction of1,4-diketones such as Formula IV can be accomplished by analogy withreported methods (see Chong, et al., Tetrahedron: Asymmetry 6:409-418(1995), L1, et al., Tetrahedron 63:8046-8053 (2007), Aldous, et al.,Tetrahedron: Asymmetry 11:2455-2462 (2000), Masui, et al.,Synlett:273-274 (1997), Jing, et al., Adv. Synth. Catal. 347:1193-1197(2005), Sato, et al., Synthesis:1434-1438 (2004)), such as reductionwith (−) or (+)-diisopinocamheylchloroborane (DIP-chloride), with boraneand an oxazaborolidine catalyst, or with asymmetric hydrogenation in thepresence of a suitable Ruthenium (II) catalyst, such as[RuCl2{(R)-BINAP}{(R,R)-DPEN}](BINAP=2,2′-bis(diarylphosphino)-1,1′-binaphthyl;DPEN=1,2-diphenylethylenediamine). The diketones IV (1 equivalent) canbe reduced by NaBH₄ (3 equivalents) in solvents such as tetrahydrofuranwith heating to about 50° C. The diketones IV (1 equivalent) can beenantioselectively reduced upon addition to a mixture made fromN,N-diethylaniline borane (about 2 equivalents), trimethylborate (about0.2 equivalents) and either (S) or (R)α,α-diphenyl-2-pyrrolidinemethanol (about 0.17 equivalents) in a solventsuch as THF at temperatures ranging from about 10° C. to about 30° C.(Synthesis 2507-2510 (2003)). The resultant racemic, enantiomericallyenriched, or meso 1,4-diols V may be reacted with methanesulfonylchloride or methanesulfonic anhydride to provide the dimesylate FormulaVI. For example, diols V (1 equivalent) can be reacted withmethanesulfonic anhydride (about 2.5 equivalents) in the presence of abase such as diisopropylethylamine (about 4 equivalents) in a solventsuch as tetrahydrofuran or 2-methyltetrahydrofuran at temperaturesstarting from about −15° C. to −25° C. and increasing to about roomtemperature. Alternatively Formula V may be converted to a ditriflate orditosylate by the action of p-toluenesulfonyl chloride or triflicanhydride, or to a dihalide such as a dibromide or dichloride by theaction of PPh₃ in the presence of CCl₄ or CBr₄, or by the action ofSOCl₂, POCl₃, or PBr₃. The dimesylate, ditriflate, ditosylate, ordihalide may be reacted with an amine, such as 4-fluoroaniline (as shownfor illustration in Scheme II), with or without a co-solvent such as DMFat room temperature to 100° C., to give the pyrrolidines such as FormulaVII. The dimesylate VI (1 equivalent) (or in the alternative theditriflate, ditosylate, or dihalide) may be reacted with between 1 to 20equiv of an amine D-NH₂, such as, for example, a substituted aniline insolvents such as tetrahydrofuran or 2-methyltetrahydrofuran with orwithout a co-solvent such as DMF, at about room temperature to about100° C., to give the pyrrolidines such as Formula VII. Where fewerequivalents of amine D-NH₂ are employed (i.e., 1-2 equivalents), a basesuch as diisopropylethylamine can be added to promote the reaction. Incertain cases, the amine can be used in a large excess (i.e., asreaction solvent). For example, the reaction of a dimesylate (1equivalent) with excess aniline (about 6.5 equivalents) can be conductedby heating to 65° C. in 2-methyltetrahydrofuran until completion of thereaction. Numerous substituted anilines can be reacted with thedimesylate Formula VI, including, but not limited to,3-fluoro-4-(piperidin-1-yl)aniline,3,5-difluoro-4-(piperidin-1-yl)aniline,3,5-difluoro-4-(4-phenylpiperidin-1-yl)aniline,3-difluoro-4-(4-phenylpiperidin-1-yl)aniline,4-(4-phenylpiperidin-1-yl)aniline, 4-cyclopropylaniline,4-cyclopropyl-2-fluoroaniline, 4-cyclopropyl-3,5-difluoroaniline,4-cyclohexyl-3-fluoroaniline, biphenyl-4-amine, 4-(pyridin-2-yl)aniline,3,5-dichloro-4-(piperidin-1-yl)aniline,4-(4,4-dimethylpiperidin-1-yl)-3,5-difluoroaniline,4-(4,4-fluoropiperidin-1-yl)-3,5-difluoroaniline,3-methyl-4-(piperidin-1-yl)aniline,2,5-difluoro-4-(piperidin-1-yl)aniline,4-(3,5-dimethylpiperidin-1-yl)-3,5-difluoroaniline,4-(2,6-dimethylpiperidin-1-yl)-3,5-difluoroaniline,2,3,5-trifluoro-4-(piperidin-1-yl)aniline,3,5-difluoro-4-(4-isopropylpiperidin-1-yl)aniline,3,5-difluoro-4-(4-methylpiperidin-1-yl)aniline,3,5-difluoro-4-(4-(trifluoromethyl)piperidin-1-yl)aniline,4-(4-tert-butylpiperidin-1-yl)-3,5-difluoroaniline,3,5-difluoro-4-(6-azaspiro[2.5]octan-6-yl)aniline,4-(2-azabicyclo[2.2.2]octan-2-yl)-3,5-difluoroaniline,4-(3,3-dimethylazetidin-1-yl)-3,5-difluoroaniline, 4-tert-butylaniline,4-ethoxyaniline, 4-phenoxyaniline, 1-(4-aminophenyl)piperidin-2-one,4-(cyclopentyloxy)-3-fluoroaniline,3-chloro-4-(trifluoromethoxy)aniline,2,5-difluoro-4-(trifluoromethyl)aniline, 4-(2,2-difluoroethoxy)aniline,4-chloroaniline, 4-(2-methoxyethoxy)aniline, 4-(oxazol-2-yl)aniline,4-(2-fluoropyridin-4-yl)aniline, 3,4-difluoroaniline,4-chloro-3-fluoroaniline, 3-fluoro-4-(methylsulfonyl)aniline,4-(3-azabicyclo[3.2.0]heptan-3-yl)-3,5-difluoroaniline,4-((3-ethyloxetan-3-yl)methoxy)aniline,4-cyclopropyl-3,5-difluoroaniline, 4-(1,3-dioxan-5-yloxy)aniline,3,5-difluoro-4-(octahydroisoindol-2-yl)aniline,4-((1,3-dioxolan-4-yl)methoxy)aniline,4-((3-ethyloxetan-3-yl)methoxy)-3,5-difluoroaniline,4-(pentafluorosulfanyl)aniline,N1-tert-butyl-2-fluorobenzene-1,4-diamine, heteroaryl amines, alkylamines, cycloalkyl amines, substituted benzylamines, allylamine, oranilines that are listed in or can be made using General Procedures 1,1.1, or 1.2. The dinitro Formula VII may be reduced to the diaminoFormula VIII using Fe in the presence of NH₄Cl, HCl, or acetic acid, orby treatment with a hydride reducing agent, such as sodium borohydride(with or without the addition of a transition metal salt, such as BiCl₃,SbCl₃, NiCl₂, Cu₂Cl₂, or CoCl₂) in a solvent such as ethanol or THF. Forexample compounds VII (1 equivalent) can be reduced to VIII by reactionwith iron powder (about 6 equivalents) and ammonium chloride in a 1:1mix of THF and ethanol with heating to about 60-80° C. Alternatively,Formula VII can be reduced to the product Formula VIII by hydrogenationin the presence of a suitable catalyst, such as a palladium or platinumcatalyst or Raney-nickel. For example reduction of VII to VIII can beeffected by exposure to 30 psig hydrogen gas in the presence ofRaney-nickel Grace 2800 in a solvent such as tetrahydrofuran withshaking. The diamine Formula VIII may be reacted with a suitablyprotected proline acid (Boc is shown, although Cbz, Troc, or Fmoc may besubstituted) in the presence of a peptide coupling reagent, such asEDAC/HOBT, PyBOP, HATU, T3P or DEPBT, in a solvent such as THF, DMF,dichloromethane, ethyl acetate, or DMSO, with or without the addition ofan amine base such as N-methylmorpholine, Hunig's base, pyridine,2,6-lutidine, or triethylamine, to give Formula IX. For example,reaction of VIII (1 equivalent) with1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (2.5 equivalents)and HATU (2.5 equivalents) in the presence of diisopropylethylamine (3equivalents) in DMSO at about room temperature can provide the productIX. Removal of the Boc protecting groups to give X may be accomplishedby treatment with an acid, such as TFA, HCl, or formic acid. Forexample, reaction of IX (1 equivalent) with TFA:CH₂Cl₂ (1:1) at roomtemperature can provide compounds X. Compounds XI may be prepared bycoupling of Formula X with an acid of choice using the standard peptidecoupling reagents and conditions described above. For example, X(1equivalent) can be reacted with acids (2 equivalents) such as, but notlimited to, 2-(methoxycarbonylamino)-3-methylbutanoic acid,2-(methoxycarbonylamino)-3,3-dimethylbutanoic acid,2-cyclohexyl-2-(methoxycarbonylamino)acetic acid,2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid, oracids listed under General Procedure 19. Alternately, diamine VIII maybe reacted directly with an appropriately N-substituted proline in thepresence of a peptide coupling reagent such as EDAC/HOBT, PyBOP, HATU,T3P, or DEPBT, in a solvent such as THF, DMF, dichloromethane, or DMSO,with or without the addition of an amine base such asN-methylmorpholine, Hunig's base, pyridine, 2,6-lutidine, ortriethylamine, to directly give compounds XI. For example, VIII (1equivalent) can be reacted directly with1-(2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidine-2-carboxylicacid (about 2 equivalents) and T3P (about 2.8 equivalents) in thepresence of diisopropylethylamine (about 5.5 equivalents) in a solventsuch as ethyl acetate at temperatures from about 0° C. to about roomtemperature to provide XI. The foregoing sequence illustrates thesynthesis of particular compounds of the invention XI having asubstituted proline group at Y and Z (i.e., R₂ and R₅ taken togetherwith the atoms to which they are attached, and R₉ and R₁₂ taken togetherwith the atoms to which they are attached, each form a 5-memberedheterocycle). It is understood that analogous synthetic procedures canbe used to make compounds of the invention where Y, Z, R₂, R_(S), R₉,and R₁₂ are other than that shown and described in Scheme II.

in each Formula within Scheme II can be replaced with

where D is defined above, and such compounds can be readily preparedaccording to the process described in Scheme II (including makingcompound XI directly from compound VIII). Likewise, compounds of FormulaXII can be prepared from compounds of Formula X or directly fromcompounds of Formula VIII.

As yet another non-limiting example, the compounds of the presentinvention can be prepared starting from compounds of Formula II andFormula III as shown in Scheme III, where A, B, D, Y, and Z are asdescribed above, using conditions similar to those described above forthe preparation of IV in Scheme II. Similarly, the resulting1,4-diketone IV may be reduced to the 1,4-diols V using the methodsdescribed above for Scheme II. The resultant racemic, enantiomericallyenriched, or meso 1,4-diols V may be converted to the dimesylate VI oralternatively to a ditriflate, ditosylate, or dihalide by the methodsdescribed above. The dimesylate VI, ditriflate, ditosylate, or dihalidemay be reacted with an amine, including but not limited to, aniline,3,5-difluoroaniline, 3,4-difluoroaniline, 4-fluoroaniline,3-fluoroaniline, 4-trifluoromethylaniline, 4-chloroaniline, heteroarylamines, alkyl amines, cycloalkyl amines, substituted benzylamines, orallylamine, under the conditions described above the give the compoundsof the invention. Alternatively, compounds such as VIII, where R is agroup such as allyl, 4-methoxybenzyl, or 2,4-dimethoxybenzyl, may betreated with reagents useful for the removal of the R group (rhodiumcatalyst such as Rh(Ph₃P)₃Cl for R=allyl, treatment with an acid such asTFA or HCl for R=4-methoxybenzyl or 2,4-dimethoxybenzyl, hydrogenolysiswith a Pd catalyst for R=substituted benzyl) to generate compounds suchas IX. Amine IX may be reacted with an aryl halide or triflate such as X(iodide shown for illustration) employing the Buchwald-Hartwig reactionin the presence of a palladium catalyst (such as Pd(OAc)₂ or Pd₂(dba)₃)and a phosphine ligand (such as triphenylphosphine or XantPhos) and abase (such as sodium bis(trimethylsilyl)amide, potassium tert-butoxide,or K₃PO₄) to give the compounds of the present invention. Alternatively,the compounds of the present invention may be obtained by reaction of IXwith an aldehyde or ketone through reductive amination in the presenceof a hydride reducing agent, such as sodium borohydride or sodiumcyanoborohydride (with or without the addition of an acid, such asacetic acid) in a solvent such as ethanol, toluene, THF, ordichloromethane. Alternatively the reductive amination may be conductedthrough the use of hydrogenation in the presence of a suitable catalyst,such as a palladium or platinum catalyst or Raney nickel. Alternatively,amine IX may react with electrophilic reagents, such as alkyl halides,or with aryl electrophiles (suitably electron deficient aryl andheteroaryl halides and triflates) through nucleophilic aromaticsubstitution reactions to give the compounds of the present invention.

As a further non-limiting example, the compounds of XIII can be preparedstarting from compounds of Formula II and Formula III as shown in SchemeIV, where X₅ in Formula II and Formula III represents a halogen (e.g.,Cl, Br, or F) or a nitro group. Additionally, each phenyl ring can besubstituted with X₁₃, wherein X₁₃ is X₅, H, alkyl, haloalkyl, alkoxy, orhaloalkoxy. The 1,4-diketones such as IV may be prepared using knownmethods described above for the preparation of IV for Scheme II. The1,4-diketones IV may be reduced to the 1,4-diols such as V by the actionof NaBH₄, LiAlH₄, or DIBAL. Alternatively, enantioselective reduction of1,4-diketone such as IV can be accomplished by the methods describedabove for the preparation of V in Scheme II. As described forIntermediate 20D, the chiral reduction may proceed with lowerstereoselectivity with an additional substituent X₁₃ on the phenyl ring.The resultant racemic, enantiomerically enriched, or meso 1,4-diols Vmay be reacted with methasulfonyl chloride or methanesulfonic anhydrideto provide the dimesylate VI. Alternatively V may be converted to aditriflate or ditosylate by the methods described above for Scheme II.The dimesylate, ditriflate, ditosylate, or dihalide may be reacted,analogously to Scheme II, with an amine D—NH₂ including but not limitedto those amines described or referred to in Scheme H to give VII. WhenX₅ in Formula VII is nitro, the nitro groups may be reduced to thetetramino product IX using Fe in the presence of NH₄Cl, HCl, or aceticacid, or with a hydride reducing agent, such as sodium borohydride (withor without the addition of a transition metal salt, such as BiCl₃,SbCl₃, NiCl₂, Cu₂Cl₂, or CoCl₂) in a solvent such as ethanol or THF.Alternatively, VII (X₅=nitro) can be reduced to the product IX byhydrogenation in the presence of a suitable catalyst, such as apalladium or platinum catalyst or Raney nickel. Alternatively, compoundsVII where X₅=halogen may be reacted with ammonia (R═H) or an aminebearing a suitable protecting group (R=substituted benzyl such as4-methoxybenzyl or 2,4 dimethoxybenzyl or R=allyl). The resultingproducts VIII may be treated with a reagent useful for the removal ofthe R protecting group (rhodium catalyst such as Rh(Ph₃P)₃Cl forR=allyl, treatment with an acid such as TFA or HCl for R=4-methoxybenzylor 2,4-dimethoxybenzyl, hydrogenolysis with a Pd catalyst forR=substituted benzyl) to give the product IX. Formula IX may be reactedwith a suitably protected proline acid (Boc is shown, although Cbz,Troc, or Fmoc may be substituted) in the presence of a peptide couplingreagent, such as EDAC/HOBT, PyBOP, HATU, T3P, or DEPBT, in a solventsuch as THF, DMF, dichloromethane, or DMSO, with or without the additionof an amine base, such as N-methylmorpholine, Hunig's base, pyridine,2,6-lutidine, or triethylamine, to give X as a mixture of the amideproducts. Although formula X depicts reaction taking place on a specificNH₂ group, the reaction may take place at either NH₂. Conversion to thebenzimidazole compound XI may be accomplished by heating X in aceticacid (50-100° C.). Alternatively, XI may be prepared by reaction of IXwith an aldehyde, followed by treatment with an oxidant, such asCu(OAc)₂ or MnO₂ (see Penning, et al., Bioorg. Med. Chem. 2008, 16,6965-6975. After removal of the Boc protecting groups from IX(accomplished by treatment with an acid, such as TFA, HCl, or formicacid), the compounds of the present invention may be prepared bycoupling of the resulting diamine XII with an acid of choice using thestandard peptide coupling reagents and conditions described above forScheme II to give XIII.

in each Formula within Scheme IV can be replaced with

where D is defined above, and such compounds can be readily preparedaccording to the process described in Scheme IV. Compounds of FormulaXIV can be similarly prepared from compounds of Formula XII. Whensubjected to synthetic processes in Scheme IV, enantiomerically enricheddiols V may produce mixtures containing varying amounts ofstereoisomeric cis and trans pyrrolidines VII. The stereoisomericpyrrolidines may be separated according to standard chromatographytechniques. Alternatively, such separations may be carried out at alater stage in the synthetic process including the steps of Schemes XIIIand XIV, or after the final step.

Alternatively IX in Scheme IV may be prepared from a compound of FormulaII as shown in Scheme V. Compound VIII from Scheme II may be treatedwith an acylating agent such as acetyl chloride or acetic anhydride togive compound II (Scheme V). Nitration of compound II to provide III maybe accomplished using known methods, such as treatment with nitric acidor potassium nitrate in the presence of an acid such as sulfuric acid ortreatment with NO₂BF₄. Removal of the acetamide protecting group may beaccomplished by treatment with Boc anhydride in the presence of DMAP togive IV, followed by sequential treatment of IV with hydroxide (such asNaOH, KOH, or LiOH) to remove the acetyl group and a strong acid such asTFA or HCl to remove the Boc protecting group to provide V. The nitrogroups in V may be reduced to amino groups using the methods describedabove for Scheme IV to provide IX.

in each Formula within Scheme V can be replaced with

where D is defined above, and such compounds can be readily preparedaccording to the process described in Scheme V.

As still another non-limiting example, the compounds of the presentinvention can be prepared starting from compounds of Formula II as shownin Scheme VI, where A, B, D, Y, and Z are as described above. A1,4-diketone compound of Formula II (prepared as described in SchemeIII) may be reacted with an amine, including but not limited to,aniline, 3,5-difluoroaniline, 3,4-difluoroaniline, 4-fluoroaniline,3-fluoroaniline, 4-trifluoromethylaniline, 4-chloroaniline, heteroarylamines, alkyl amines, cycloalkyl amines, substituted benzylamines, orallylamine, under acid catalyzed conditions, such as acetic acid, TFA,formic acid or HCl, to give the compounds of the invention.

As a further non-limiting example, the compounds of the presentinvention can be prepared from a compound of Formula II as shown inScheme VII. A compound of Formula II, where R_(X) is a halogen, such asbromo, chloro, or iodo, or a triflate or a nonaflate may be converted toa boronic acid or ester such as Formula III, using the chemistryanalogous to that of Scheme II to prepare VII (in Scheme II); forexample, by starting with 1-(4-bromophenyl)ethanone and2-bromo-1-(4-bromophenyl)ethanone. A compound of Formula II, where R_(X)is a halogen, such as bromo, chloro, or iodo, or a triflate or anonaflate may be converted to a boronic acid or ester such as FormulaIII, (e.g., a cyclic pinacolate ester) where R is hydrogen, methyl,ethyl, or a cyclic pinacolate ester. For example a compound of FormulaII can be transformed to a compound of III by treatment withpinacol-borane in the presence of a catalyst such as, for example,tris(dibenzylidineacetone)palladium (0), and a ligand such as, forexample, tri-t-butylphosphine, in solvents such as, for example,tetrahydrofuran, dioxane, or toluene at temperatures ranging fromambient to about 130° C. Alternatively, compound II can be reacted withbis(pinacolato)diboron in the presence of a catalyst such as, forexample, Combiphos-Pd6 (CombiPhos Catalysts, Inc. (NJ, USA),dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct, or palladium acetate in the presence of a ligandsuch as, for example,2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos), and abase such as, for example, potassium acetate in solvents such as, forexample, toluene, dioxane, tetrahydrofuran, dimethylformamide ordimethyl sulfoxide at temperatures from about 60 to about 130° C. togive compound III. Alternatively, a compound of Formula II may bereacted with an organolithium reagent, such an n-BuLi, sec-BuLi, ort-BuLi, followed by reaction with trimethyl borate or triethyl borate,to give a compound of Formula III.

A compound of Formula III in Scheme VII can be coupled with a compoundof Formula IV, where R_(Y) is a halogen, such as bromo, chloro or iodo,under Suzuki reaction conditions to provide a compound of Formula V.Such conditions include, for example, use of a palladium catalyst suchas, for example, tris(dibenzylidineacetone)palladium (0), palladiumacetate, bis(triphenylphosphine)palladium (II) chloride,tetrakis(triphenylphosphine)palladium, ordichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct; base such as, for example, potassium carbonate,potassium phosphate, potassium t-butoxide, sodium carbonate, cesiumcarbonate, or cesium fluoride; and solvent such as, for example,toluene, ethanol, water, or tetrahydrofuran, or mixtures thereof heatedin the temperature range from about 40 to about 130° C.

Removal of the Boc protecting groups from V may be accomplished bytreatment with an acid, such as TFA, HCl, or formic acid. Certaincompounds of the present invention such as VI may be prepared bycoupling the resulting amino compounds with an acid of choice using thestandard peptide coupling reagents, such as EDAC/HOBT, PyBOP, HATU, orDEPBT, in a solvent such as THF, DMF, dichloromethane, or DMSO, with orwithout the addition of an amine base such as N-methylmorpholine,Hunig's base, pyridine, 2,6-lutidine, or triethylamine. Each R_(z) isindependently -L_(Y)′-M′—R_(D) (e.g., -L_(Y)-N(R_(B)″)C(O)-L_(S)-R_(E)),and D, L₃, R₁, R₂, R₅, L_(Y), R_(B)″, L_(S), R_(E), L_(Y)′, M′ and R_(D)are as defined above. Alternatively, the functionality of T-R_(D) cansimilarly be introduced following removal of the Boc protecting groupsin V give compounds of Formula VII.

As another non-limiting example, the compounds of the present inventioncan be prepared according to Scheme VIII starting from the compound ofFormula II, initially cleaving the diol in oxidative fashion followed bysubsequent acid hydrolysis of the acetonide. This dialdehydeintermediate is then treated with an aryl boronate or aryl boronic acid(compound IV where A and Y are as described previously, or compound VII)and aniline III (where W is R_(M) or J, and R_(M) and J are as definedabove) resulting in the formation of Formula V or Formula VIIIrespectively. Formula V can be derivatized by deprotonating the hydroxylgroups with a strong base such as sodium hydride, butyl lithium, orpotassium hydride, followed by alkylation with R_(S)-halogen.Alternatively Formula VIII can be deprotonated with a strong base (e.g.,sodium hydride) and alkylated with R_(S)-halogen as well, followed byacid hydrolysis of the phenol protecting groups. The sulfonylation ofthe phenols with nonafluorobutylsulfinyl fluoride in the presence of aneutralizing agent such as potassium carbonate in a polar aproticsolvent such as DMF, followed by heating provides a compound of FormulaIX. Boronate of Formula X is produced by heating Formula IX withbis(pinacolato)diboron in the presence of X-phos and a palladiumcatalyst, such as Pd2(dba)3 and a base such as potassium acetate in anorganic solvent such as dioxane. Formula X is further derivatized tofinal product by heating a suitably substituted heteroarylhalide in thepresence of a palladium catalyst such as PdCl2(dppf) in the presence ofa base such as sodium carbonate in a mixture of toluene and ethanol.R_(S) is as defined above.

in each Formula within Scheme VIII can be replaced with

where D is defined above, and such compounds can be readily preparedaccording to the process described in Scheme VIII.

As yet another non-limiting example, the compounds of the presentinvention can be prepared according to Scheme IX starting from thecompounds of Formula II and Formula III. Formula III carboxylic acid isactivated towards coupling using reagents such as isobutylchloroformate,DCC, EDAC, or HATU in the presence of an organic base, such asdiisopropylethylamine. Upon activation, dianiline of Formula II is addedto the reaction, with the isolation of an intermediate amide, which isheated in acetic acid, preferably at 60° C., to yield the compound ofFormula IV. The benzimidazole of Formula IV is treated with SEM-Cl inthe presence of a base in an aprotic solvent such as THF, yielding twoprotected benzimidazole regioisomers V. The boronate esters VI areproduced by heating Formula V with bis(pinacolato)diboron in thepresence of a palladium catalyst, such as PdCl2(dppf), X-Phos, and abase such as potassium acetate in an organic solvent such as dioxane.Heating yields both benzimidazole regioisomers VI. Diol VII is cleavedin oxidative fashion followed by subsequent acid hydrolysis of theacetonide. This dialdehyde intermediate is then treated with an arylboronate VI and aniline VIII (where W is R_(M) or J, and R_(M) and J areas defined above) resulting in the formation of the 3 benzimidazoleregioisomers of Formula IX. Formula X is produced by deprotonating thehydroxyl groups with a strong base such as sodium hydride, butyllithium, or potassium hydride, followed by alkylation withR_(S)-halogen, followed by acid hydrolysis of the pyrrolidine andbenzimidazole protecting groups, preferably by treatment with mineralacid, such as hydrochloric acid in an alcoholic solvent such asmethanol. The carboxylic acid R_(Z)—COOH is activated towards couplingusing reagents such as isobutylchloroformate, DCC, EDAC, or HATU in thepresence of an organic base, such as diisopropylethylamine. Uponactivation, Formula X is added to the reaction, with the isolation ofFormula XI.

in each Formula within Scheme IX can be replaced with

where D is defined above, and such compounds can be readily preparedaccording to the process described in Scheme IX.

Certain compounds of the invention of general formula (8), where R₂₀ is-L_(S)′-M′-L_(S)″—R_(D) and D is as described above, can be preparedaccording to the methods of Scheme X. The bromoalkylketone (1) can bereacted with an arylalkylketone (2) using the Lewis acid mediatedconditions, described above in Scheme II, to give the diaryldiketone(3). The diketone (3) can be converted to the bisboronate (4) byreaction with bis(pinacolato)diborane in the presence of a base such aspotassium acetate, a catalyst such as PdCl₂(dppf)-CH₂Cl₂, in a solventsuch as DMSO, dimethoxyethane or dioxane with heating to between 60-100°C. Bisboronate (4) can be converted to the intermediate (5) by Suzukireaction using, in analogous fashion, the Suzuki conditions described inScheme VII. The intermediate (5) can be converted to (6) by reactionwith an amine D—NH₂ under the analogous conditions described in SchemeVI. For example, reaction of (5) with D—NH₂ in the presence of an acidsuch as, but not limited to, TFA, in a solvent such as, but not limitedto, toluene and with heating up to 110° C. can provide intermediates ofgeneral structure (6). Compounds (6) can be converted to compounds ofgeneral formulas (7) and then (8) using, in analogous fashion, themethods described in Scheme VII. Alternatively, the functionality ofT-R_(D) can be similarly introduced to compounds of Formula (7) to givecompounds of Formula (X-1).

The intermediates (6) can also be prepared using the route depicted inScheme XI. The intermediate (3) can be reacted with an amine D—NH₂using, in analogous fashion, the conditions described in Schemes VI andX to provide intermediates (9), which can be converted to (10) using,analogously, conditions as described above in Scheme X; and (10), inturn, can be converted to compounds (6) using the Suzuki reactionconditions described in Scheme VII.

As still another non-limiting example, the compounds of the invention ofgeneral formula (15), where R₂₀ is -L_(S)′-M′-L_(S)″—R_(D) and D is asdescribed above, can be prepared as shown in Scheme XII. A 1,4-diketonecompound (3) may be reacted with an amine D-NH₂, under acid catalyzedconditions, such as acetic acid, TFA, formic acid or HCl, to give thecompounds (11). For example, a diketone (3) (1 equivalent) can bereacted with an aniline (1.2 equivalents) and TFA (2 equivalents) in asolvent such as toluene with heating to between around 80 and 120° C. toprovide the compounds (11). Alternatively, a diketone (3) can be reactedwith an aniline (about 10 equivalents) with heating in acetic acid toaround about 70° C. to provide the compounds (11). Amines that can bereacted according to the foregoing description include but are notlimited to, those amines described or referred to in Scheme II assuitable for reacting with intermediate (5). Compounds of formula (11)can be converted to compounds of formula (12) by reduction with iron inthe presence of ammonium chloride. For example, reaction of compounds(11) (1 equivalent) with iron powder (about 6 equivalents) in thepresence of ammonium chloride (about 3 equivalents) in a mixed solventof ethanol:THF:water (1:1:0.25) at reflux can provide compounds (12).The conversion of (11) to (12) may also be effected by other methodsdescribed above in Scheme II to convert VII to VIII, for example bycatalytic hydrogenation. Compounds (12) (1 equivalent) can be convertedto compounds (13) using the peptide coupling condition described for theconversion of VIII to IX in Scheme II, for example using EDAC/HOBt (2equivalents) and an appropriate acid in solvents such as DMF at aroundroom temperature. Compounds (13) can be converted to compounds (14)using TFA/CH₂Cl₂ as described above for converting IX to X in Scheme II.Compounds (14) can be converted to compounds (15) using proceduresanalogous to those in Scheme II to convert X to XI, such as the couplingprocedure to convert (12) to (13). Alternatively, the functionality ofT-R_(D) can be similarly introduced to compounds of Formula (14) to givecompounds of Formula (XII-1).

Compounds of general formula (19), where D is as described above, can beprepared according to the methods of Scheme XIII. Compounds of generalformula (16) can be converted to compounds of general formula (17) usinga Buchwald reaction withtert-butyl-2-carbamoylpyrrolidine-1-carboxylate. This Buchwald reactioncan be conducted in the presence of a base (e.g., cesium carbonate), apalladium catalyst (e.g., tris(dibenzylideneacetone)dipalladium(0)), aphosphine ligand (e.g., 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)in solvent such as dioxane with heating to about 80-120° C. Theintermediate (17) can be reduced to (18) and cyclized to (19) using, inanalogous fashion, the conditions described generally in Scheme IV.Compounds (19) can be further reacted as illustrated in Scheme IV toprovide compounds of the invention. Each phenyl ring in the abovestructures can be substituted with X₁₃, wherein X₁₃ is H, halogen,alkyl, haloalkyl, alkoxy, or haloalkoxy. Mixtures of cis and transstereoisomeric pyrrolidines in Scheme XIII may be separated into the cisand trans isomers using standard chromatographic techniques.

Certain compounds of the invention of general formula (23), where D isas described above, can be prepared according to the methods of SchemeXIV. Compounds (16) can be reacted with compound (20) using a Buchwaldreaction as described generally in Scheme XIII to provide compounds(21). Compounds (21) can be reduced to compounds (22) and cyclized to(23) using, in analogous fashion, the conditions described generally inthe foregoing Schemes.

Certain compounds of the invention of general formula (29), where R₂₀ is-L_(S)′-M′-L_(S)″—R_(D) and D is as described above, can be preparedaccording to the methods of Scheme XV. Compounds of formula (24) can beconverted to compounds of formula (25) (Sonogashira reaction) byreaction with trimethylsilylacetylene, a palladium catalyst (e.g.,bis(triphenylphosphine)palladium(II)chloride), a copper catalyst (e.g.,copper(I)iodide), and a base (e.g., triethylamine) wherein an amine basecan also be used as solvent. The compounds (25) can be desilylated tocompounds (26) by reaction with a fluoride source (e.g.,tetrabutylammonium fluoride) in a solvent such as THF. Compounds (26)can be converted to compounds (27) by formation of the dianion of (26)with n-butyllithium and subsequent reaction with a Weinreb amide (e.g.,N-(tert-butoxycarbonyl)-L-proline-N′-methoxy-N′ methylamide). Thisreaction can be conducted in an appropriate solvent such as THF ordimethoxyethane. Compounds (27) can be converted to compounds (28) byreaction with hydrazine in a solvent such as ethanol. The compounds (28)can be converted to compounds (29) using the methods described generallyin the foregoing Schemes. Alternatively, the functionality of T-R_(D)can be similarly introduced to compounds of Formula (28) to givecompounds of Formula (XV-1).

Certain compounds of the invention of general formula (34), where R₂₀ is-L_(S)′-M′-L_(S)″—R_(D) and D is as described above, can be preparedaccording to the methods of Scheme XVI. Compounds (24) can be convertedto compounds (30) by reaction of (24) with CO(g) under pressure (ca. 60psi) in the presence of a palladium catalyst (e.g., PdCl₂(dppf)) inmethanol as solvent and with heating to around 100° C. Compounds (30)can be converted to compounds (31) by reaction with hydrazine in asolvent such as methanol with heating to about 60-80° C. Compounds (31)can be converted to compounds (32) by reaction withN-Boc-2-cyano-pyrrolidine in the presence of a base (e.g., potassiumcarbonate) in a solvent such as butanol and with heating to around 150°C. with irradiation in a microwave reactor. Compounds (32) can bedeprotected to compounds (33) and acylated to (34) using, in analogousfashion, the conditions described generally in the foregoing Schemes.Alternatively, the functionality of T-R_(D) can be similarly introducedto compounds of Formula (33) to give compounds of Formula (XVI-1).

Certain compounds of the invention of general formula (38), where R₂₀ is-L_(S)′-M′-L_(S)″—R_(D) and D is as described above, can be preparedaccording to the methods of Scheme XVII. Compounds of formula (24) canbe converted to compounds (35) by reaction with CuCN in a solvent suchas DMF and with heating to about 160° C. with microwave irradiation.Compounds (35) can be converted to compounds (36) by reaction withHCl(g) in anhydrous methanol at 0° C. with warming to room temperature.Compounds (36) can be converted to compounds (37) by reaction withNH₃(g) in anhydrous methanol at 0° C. with warming to room temperature.Compounds (37) can be converted to compounds (38) by reaction with (41)in THF in the presence of a base (e.g., potassium carbonate).Alternatively, the functionality of T-R_(D) can be similarly introducedto compounds of Formula (33) to give compounds of Formula (XVII-1).

Compounds of formula (41), where R₂₀ is -L_(S)′-M′L_(S)″—R_(D), can beprepared using the methods of Scheme XVIII. Compounds (39) can beconverted to compounds (40) by sequential reaction of (39) withisobutylchloroformate in THF at 0° C. followed by diazomethane.Compounds (40) can be converted to compounds (41) by reaction with HBrin acetic acid. Similarly, compounds of formula (XVIII-1) can beconverted to compounds of formula (XVIII-2) and then (XVIII-3), whereinT-R_(D) are as defined above.

Certain compounds of the invention of general formula (48), where R₂₀ is-L_(S)′-M′-L_(S)″—R_(D) and D is as described above, can be preparedaccording to the methods of Scheme XIX. Compound (42) can be reactedwith compound (43) using, in analogous fashion, the Lewis acid mediatedconditions described above in Scheme II to provide compound (44).Compound (44) can be converted sequentially to the diol (45), themesylate (46) and the cyclic intermediate (47) using, in analogousfashion, the conditions of Scheme II. Compounds (47) can be converted tocompounds (48) by reaction with (20) under Buchwald conditions such asthose referred to Scheme XIV and described in Scheme XIII.Alternatively, the functionality of T-R_(D), wherein T and R_(D) are asdefined above, can be similarly introduced to compounds of Formula (47)to give compounds of Formula (XIX-1).

Certain compounds of the invention of general formula (55), where R₂₀ is-L_(S)′-M′-L_(S)″—R_(D) and D is as described above, can be preparedaccording to the methods of Scheme XX. Diethyl meso-2,5-dibromoadipate(49) can be reacted with an amine D—NH₂ in a solvent such as THF,dioxane, or dimethoxyethane with heating from 50-100° C. to givecompounds (50). Compounds (50) can be converted to (51) by alkalinehydrolysis with a base (e.g., NaOH, KOH) in an alcohol (e.g., methanol,ethanol) and water mixture for solvent. Compounds (51) can be convertedto (52) by reaction first with oxalylchloride, and treatment of theintermediate acid chloride with diazomethane at 0° C. Compounds (52) canbe converted to (53) by reaction with aqueous HBr. Compounds (53) can beconverted to compounds (54) by reaction with thiourea in ethanol or likesolvent. Compounds (54) can be converted to compounds (55) using, inanalogous fashion, the conditions described above in Scheme II.Similarly, the functionality of T-R_(D), wherein T and R_(D) are asdefined above, can be introduced to compounds of Formula (54) to givecompounds of Formula (XX-1).

Certain compounds of the invention of general formula (60), where R₂₀ is-L_(S)′-M′-L_(S)″—R_(D) and D is as described above, can be preparedaccording to the methods of Scheme XXI. Compound (56) can be reactedwith compound (57) in pyridine with heating to about 135° C. to formcompound (58). Compound (58) can be converted to compounds (59) byreaction of an amine D-NH₂ with POCl₃ followed by addition of (58) andheating at about 200° C. in 1,2-dichlorobenzene. Compounds (59) can beconverted to compounds (60) using, in analogous fashion, the conditionsdescribed above in Scheme VII. Similarly, the functionality of T-R_(D),wherein T and R_(D) are as defined above, can be introduced to compoundsof Formula (59) to give compounds of Formula (XXI-1).

Certain compounds of the invention of general formula (66), where R₂₀ is-L_(S)′-M′-L_(S)″—R_(D) and D are as described above, can be preparedaccording to the methods of Scheme XXII. Compounds of general formula(61) can be reacted with borontribromide in dichloromethane at 0° C. togive compounds (62), which can be subjected to hydrogenation conditionsusing platinum(II) oxide to give compounds (63). Coupling betweencompounds (63) and proline derivatives (64) can be carried out usingstandard coupling conditions described above to give compounds (65),which can be converted to (66) by the action of diethylazodicarboxylateand triphenylphosphine in THF.

Certain compounds of the invention of general formula (74), where R₂₀ is-L_(S)′-M′-L_(S)″—R_(D) and D is as described above, can be preparedaccording to the methods of Scheme XXIII. Compound (67) can be convertedto (68) by reduction of the nitro group using tin(II) chloride inethanol. Compound (69) can be made from (68) by peptide coupling withBoc-proline, followed by heating of the resulting amide in acetic acidat 80° C. Compound (69) can be reacted with SEM-Cl anddiisopropylethylamine in dichloromethane to give (70), which can becoupled with (71) using a palladium catalyst such as PXPd using a basesuch as cesium fluoride in a solvent such as N,N-dimethylformamide at100° C. to give (72). Compound (72) can be converted to (73) by reactionwith Selectfluor in a mixture of THF and water, followed byhydrogenation using 3% Pt on carbon in ethylacetate and then reductionusing sodium borohydride in methanol. Compound (73) can be reacted withmethanesulfonyl chloride and triethylamine in dichloromethane at −10°C., followed by addition of an amine (H₂N-D) to give an intermediatethat can be converted to (74) by deprotection using 4 N HCl in1,4-dioxane and then coupling with R₂₀CO₂H using peptide couplingprocedures described above. Similarly, the functionality of T-R_(D),wherein T and R_(D) are as defined above, can be introduced to compoundsof Formula (73) to give compounds of Formula (XXIII-1).

Certain compounds of the invention of general formula (81), where R₂₀ is-L_(S)′-M′-L_(S)″—R_(D) and D is as described above, can be preparedaccording to the methods of Scheme XXIV. Compound (75) can be convertedto (76) using SnCl₂ in ethanol. Additionally, the phenyl ring ofcompound (75) can be substituted with X₁₃ at any position substitutedwith hydrogen or fluorine, wherein X₁₃ is H, alkyl, haloalkyl, alkoxy,or haloalkoxy, and those compounds carried through the subsequentsequence. Coupling of (76) with (64) using peptide coupling proceduresdescribed above to give an amide that can be heated in acetic acid at100° C. to give (77). Compound (77) can be reacted with SEM-Cl anddiisopropylethylamine in dichloromethane to give (78). For convenientillustration, the SEM protecting groups on the benzimidazoles are shownattached to particular nitrogens of the benzimidazole. The actualsubstitution positions of the SEM groups may be at either nitrogen(i.e., (78) may be a mixture of regioisomers). In subsequent compounds(79) through (80), the positional isomerism of the SEM group results inmixtures of SEM regioisomers that may or may not be separable. Inpractice the SEM regioisomers can be carried through as mixtures.Compound (78) can be reacted with (71) as described above to give (79).Compound (79) can be converted to (80) using Selectfluor in a mixture ofTHF and water, followed by hydrogenation with Pt on carbon inethylacetate and reduction with sodium borohydride in methanol or chiralreduction conditions with (S) or (R) α,α-diphenyl-2-pyrrolidinemethanol,diethylaniline borane and trimethylborane. Compound (80) can beconverted to compounds (81) by mesylation with methanesulfonyl chlorideand triethylamine at temperatures less than 0° C., followed by reactionwith primary amine H₂N-D and deprotection using 4 N HCl in 1,4-dioxane.Similarly, the functionality of T-R_(D), wherein T and R_(D) are asdefined above, can be introduced to compounds of Formula (77) to givecompounds of Formula (XXIV-1) at the end of the synthetic sequence.

Certain amines, D—NH₂, in the foregoing Schemes are represented byformula (84), and may be prepared according to the general method shownin Scheme XXV, wherein R_(N) is as defined above (e.g., halogen, alkyl,haloalkyl) and R_(M) is —N(R_(S)R_(S)) (e.g., —NEt₂), heterocyclyl(e.g., pyrrolidin-1-yl, piperidin-1-yl,

etc., wherein G₃ is defined above,

is a nitrogen containing heterocycle substituted with G₃, and

is a nitrogen containing bridged, bicyclic heterocycle), or —OR_(S)(e.g., —O-t-butyl, —O-isopropyl, etc.). Fluoronitrobenzenes (82) can bereacted with an appropriate amine in the presence of dibasic potassiumphosphate in a solvent such as DMSO optionally with heating to giveintermediates (83), wherein R_(M) is —N(R_(S)R_(S′)) (e.g., —NEt₂) orheterocyclyl (e.g., pyrrolidin-1-yl, piperidin-1-yl,

etc.). Fluoronitrobenzenes (82) can also be reacted with alkali metalalkoxides (e.g., potassium tert-butoxide) to give intermediates (83),wherein R_(M) is —OR_(S) (e.g., —O-t-butyl, —O-isopropyl, etc.).Intermediates (83) may be converted to (84) using well-known nitroreduction conditions. For example, (83) can be converted to (84) bycatalytic hydrogenation using palladium on carbon. Alternatively, (83)can be converted to (84) by reaction with iron/ammonium chloride inTHF/methanol/water as solvent. Other conditions for effecting nitroreduction include those described in the foregoing schemes and thosegenerally known to one skilled in the art.

Certain compounds of the present invention (XXVI-10) can be prepared asshown generally in Scheme XXVI, where D, T, and R_(D) are as describedabove. Reaction of compounds (1) with compounds (III), using theconditions described generally in Scheme II for the preparation ofcompounds (IV), can provide diketone compounds (XXVI-1). Compounds(XXVI-1) can be converted to compounds (XXVI-2) using the generalconditions of Scheme II for the conversion of (IV) to (V). Compounds(XXVI-2) can be converted to compounds (XXVI-3) using the generalconditions of Scheme II for the conversion of (V) to (VI). Compounds(XXVI-3) can be converted to compounds (XXVI-4) using the generalconditions of Scheme II for the conversion of (VI) to (VII). Compoundsof formula (XXVI-4) can be converted to compounds (XXVI-5) using thegeneral conditions of Scheme VII for the conversion of (II) to (III).Compounds (XXVI-5) can be converted to compounds (XXVI-6) using thegeneral conditions of Scheme VII for the conversion of (III) to (IV).Compounds (XXVI-6) can be converted to compounds (XXVI-7) using thegeneral conditions of Scheme II for the conversion of (VII) to (VIII).For example, compounds (XXVI-6) (1 equivalent) can be reduced withhydrogen gas (1 atm) in the presence of PtO₂ (about 0.2 equivalents) ina solvent such as ethanol:THF (1:1). Compounds (XXVI-7) can be convertedto compounds (XXVI-8) using the methods described generally in Scheme IIfor conversion of (VIII) to (IX). For example, reaction of (XXVI-7) (1equivalent) with 1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid(1.5 to 3 equivalents) and HATU (about 1.6 equivalents) in the presenceof diisopropylethylamine (3 equivalents) in DMSO at about roomtemperature can provide the compounds (XXVI-8). Compounds (XXVI-8) canbe converted to compounds (XXVI-9) using the methods described generallyin Scheme II for conversion of (IX) to (X). For example, reaction of(XXVI-8) (1 equivalent) with HCl in dioxane at about room temperaturecan provide the compounds (XXVI-9). Compounds (XXVI-9) can be convertedto compounds (XXVI-10) by reaction with an appropriate acid using themethods described generally in Scheme II for the conversion of (X) to(XI). For example, reaction of (XXVI-9) (1 equivalent) with2-(methoxycarbonylamino)-3-methylbutanoic acid (about 2 to 3equivalents), HATU (about 2.5 to 3.5 equivalents), anddiisopropylethylamine (about 10 equivalents) in a solvent such as DMSOcan provide the products (XXVI-10).

Certain compounds of the present invention (XXVII-7) can be prepared asshown generally in Scheme XXVII, where D, T, and R_(D) are as describedabove. Compounds (XXVI-1) can be converted to compounds (XXVII-1) usingthe general conditions of Scheme XII for the conversion of (3) to (11).Compounds (XXVII-1) can be converted to compounds (XXVII-2) by reductionusing conditions described generally above in Scheme II. For example(XXVII-1) (1 equivalent) can be reduced with iron powder (about 6equivalents) and ammonium chloride (about 3 equivalents) inethanol:THF:water (1:1:0.25) with heating up to the reflux temperatureto provide (XXVII-2). Compounds (XXVII-2) can be converted to compounds(XXVII-3) using the conditions described above for conversion of VIII toIX in Scheme II, (12) to (13) in Scheme XII, or (XXVI-7) to (XXVI-8) inScheme XXVI. Compounds (XXVII-3) can be converted sequentially tocompounds (XXVII-4) and (XXVII-5) using the methods and conditionsdescribed generally in Scheme VII for the conversion of (II) to (III) to(V). Compounds (XXVII-5) can be converted sequentially to compounds(XXVII-6) and (XXVII-7) using the methods and conditions describedgenerally above, for example using the methods to convert (IX) to (X) to(XI) in Scheme II.

Certain compounds of the invention of general formula (XXVIII-7), whereD, T, and R_(D) are as described above, can be prepared according to thesequence of Scheme XXVIII. Compounds (XXVIII-1) can be prepared from2-bromo-1-(4-nitrophenyl)ethanone, 1-(4-chloro-3-nitrophenyl)ethanone,and an amine D—NH₂ according to the methods described above to preparecompounds (VII) in Scheme II, (XXVI-4) in Scheme XXVI, nd (VII) inScheme IV. Compounds (XXVIII-1) (1 equivalent) can be converted tocompounds (XXVIII-2) by reaction with neat 4-methoxybenzylamine (about4-6 equivalents) with heating to around 140-150° C. Compounds (XXVIII-2)can be converted to compounds (XXVIII-3) by reduction according to theconditions described generally in Scheme II to prepare compounds (VIII).For example, reaction of (XXVIII-2) (1 equivalent) with PtO₂ (about0.4-0.5 equivalents) in a solvent such as ethanol:THF (1:1) under ahydrogen atmosphere (1-4 atm) can provide compounds (XXVIII-3).Compounds (XXVIII-3) can be converted to compounds (XXVIII-4) accordingto the conditions described generally in Scheme II to prepare compounds(IX). For example, reaction of (XXVIII-3) (1 equivalent) with1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (about 2-3equivalents), HATU (about 2-3 equivalents), and diisopropylethylamine(about 3 equivalents) in a solvent such as DMSO at room temperature canprovide compounds (XXVIII-4). Compounds (XXVIII-4) (1 equivalent) can beconverted to compounds (XXVIII-5) by reaction with DDQ (about 1.2equivalents) in a solvent mixture of CH₂Cl₂:water (20:1) at roomtemperature. Compounds (XXVIII-5) can be converted to compounds(XXVIII-6) according to the general methods described in Scheme IV toprepare compounds (XI) (e.g., heating in acetic acid to around 60-70°C.). Compounds (XXVIII-6) can further be converted to compounds(XXVIII-7) by using the standard deprotection and coupling methodsreferred to in Scheme IV to prepare compounds (XIII) or (XIV).

Certain compounds of the invention (XXIX-9) where D, T, and R_(D) are asdescribed above, can be prepared according to the sequence of SchemeXXIX. Compounds (XXIX-1) can be prepared from2-bromo-1-(4-bromophenyl)ethanone, 1-(4-chloro-3-nitrophenyl)ethanone,and an amine D—NH₂ according to the methods described above to preparecompounds (VII) in Scheme II, (XXVI-4) in Scheme XXVI, and (VII) inScheme IV. Compounds (XXIX-1) (1 equivalent) can be converted tocompounds (XXIX-2) by reaction with neat 3,4-dimethoxybenzylamine (about10 equivalents) with heating up to around 140-150° C. Compounds (XXIX-2)can be converted to compounds (XXIX-3) by reduction according to theconditions described generally in Scheme II to prepare compounds (VIII).For example, reaction of (XXIX-2) (1 equivalent) with PtO₂ (about 0.1equivalent) in a solvent such as ethanol:THF:EtOAc (1:1) under ahydrogen atmosphere (e.g., 1 atm) can provide compounds (XXIX-3).Compounds (XXIX-3) can be converted to compounds (XXIX-4) according tothe conditions described generally in Scheme II to prepare compounds(IX). For example, reaction of (XXIX-3) (1 equivalent) with asubstituted proline like(S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidine-2-carboxylicacid (about 1.2-1.5 equivalents), HOBt (about 1.2-1.5 equivalents), EDAC(about 1.2-1.5 equivalents), and N-methylmorpholine (about 5-6equivalents) in a solvent such as DMF at room temperature can providecompounds (XXIX-4). Compounds (XXIX-4) can be deprotected to compounds(XXIX-5) by reaction with excess TFA in solvents such as methylenechloride at about room temperature. Compounds (XXIX-5) can be convertedto compounds (XXIX-6) according to the general methods described inScheme IV to prepare compounds (XI) (e.g., heating in acetic acid toaround 60-80° C.). Compounds (XXIX-6) can be converted to compounds(XXIX-7) according to the general conditions of Scheme VII to preparecompounds (1II). For example, reaction of (XXIX-6) (1 equivalent) withPdCl₂(dppf) (about 0.1 equivalent), potassium acetate (about 3-5equivalents), and bis(pinacolato)diboron (about 3 equivalents) in asolvent such as toluene with heating to 80-100° C. can provide compounds(XXIX-7). Compounds (XXIX-7) can be converted to compounds (XXIX-8)according to the general conditions of Scheme VII to prepare compounds(V). For example, reaction of compounds (XXIX-7) (1 equivalent) withIntermediate 1D (about 2 equivalents), 1M sodium carbonate (about 3equivalents), and PdCl₂(dppf) (about 0.1 equivalent) in a solvent suchas toluene at around 80-100° C. can provide compounds (XXIX-8).Compounds (XXIX-8) can further be converted to compounds (XXIX-9) byusing the standard deprotection (e.g., HCl/dioxane) and coupling methods(e.g., carboxylic acid, HOBt, EDAC, and N-methylmorpholine) referred toin Scheme IV to prepare compounds (XIV).

Certain compounds of the present invention (XXX-8) can be prepared asshown in Scheme XXX. An ester (XXX-1) can be reacted with a suitablereducing agent such as DIBAL-H, in a solvent such as THF,dichloromethane, or diethyl ether, to the corresponding alcohol thenoxidized to the aldehyde (XXX-2) by employing a suitable oxidizing agentsuch as PDC in a solvent such as dichloromethane, THF or diethyl ether.A pyrrole of formula (XXX-4) can be prepared by reacting (XXX-3)(available from an aniline, an aldehyde and KCN using the Streckerreaction) together with aldehyde (XXX-2) with a base such as potassiumhydroxide in a solvent such as ethanol (Synlett, 2003, pp 1427-1430).The bromine atoms in the pyrrole compounds (XXX-4) can be converted to abis-borane compound (XXX-5) by utilization of palladium catalysis asdescribed above in Scheme VII. The pyrrole compounds (XXX-5) can bereacted with bromoimidazoles like Intermediate 1D using Suzuki reactionconditions to give the phenylimidazole (XXX-6). A variety of reactionconditions are well known to those of skill in the art to be effectivein mediating the Suzuki reaction. In particular, the reaction to produce(XXX-6) can be performed with Pd(dppf)Cl₂ catalyst and potassiumcarbonate in a mixture of toluene and water and with heating to about100° C. Removal of the Boc protecting groups to give (XXX-7) can beaccomplished by treatment with an acid, such as TFA, HCl, or formicacid. Certain compounds of the present invention (XXX-8), wherein T,R_(D), and D are as described above, may be prepared by coupling of(XXX-7) with an acid of choice using the standard peptide couplingreagents and conditions described above.

The present invention also contemplate Schemes XXXI-XXXIII to make acompound of the invention. For instance, compounds of the invention(XXXI-5) may be prepared using the sequence of steps outlined generallyin Scheme XXXI. This sequence parallels that of Scheme XXX. A compound(XXXI-1) may be converted to a compound (XXXI-2) by sequential Heckreaction with ethylacrylate followed by reduction to an aldehyde(XXXI-2). An aldehyde like (XXXI-2) may be reacted with a compound(XXX-3) analogously to the conditions of Scheme XXX to provide compounds(XXXI-3). Compounds (XXXI-3) in turn may be converted to boronatecompounds (XXXI-4) using the condition described above generally inScheme VII. Compounds (XXXI-4) may be converted to compounds (XXXI-5)over several steps including Suzuki reaction, deprotection and couplingas described generally in the foregoing Schemes.

As described in Meyer et al. Synthesis, 2005, pp. 945-956 and Meyer etal Synlett, 2003, pp 1427-1430, substituted α-aminonitriles can bereacted with α,β-unsaturated carbonyl compounds to provide substitutedhydroxy-cyano pyrrolidines. In analogous fashion, a compound (XXXII-1)may be reacted with an α,β-unsaturated aldehyde (XXXII-2) to give apyrrolidine (XXXII-3). The hydroxy and cyano groups of compounds such as(XXXII-3) may be reduced off using reagents such as NaBH₃CN or NaBH₃CNwith FeSO₄ as described in Synthesis, 2005, pp. 945-956. The nitro groupof compounds such as (XXXII-3) may be reduced using standard conditionssuch as catalytic hydrogenation or reduction with iron powder andammonium chloride. Typical nitro reduction conditions are describedelsewhere herein. The Boc group of compounds such as (XXXII-3) may beremoved using standard conditions such as with TFA/CH₂Cl₂ or HCl indioxane. Compounds such as (XXXII-4) may be reacted with an appropriateN-protected proline acid under standard conditions as describedelsewhere herein to give compounds (XXXII-5). Compounds such as(XXXII-5) may be deprotected and coupled with an acid of choice asdescribed herein to give compounds (XXXII-6) wherein T, R_(D), and D areas described herein.

Further compounds of the invention may be prepared as generally outlinedin Scheme XXXIII. Compounds such as (XXXIII-1) may be prepared from4-nitro-o-phenylenediamine by acylation with a protected proline acid(see Tetrahedron 2003, pp 2701-2712), cyclization (see Tet. Lett. 2003,5807-5810), SEM protection, and nitro reduction. Compounds such as(XXXIII-1) may be converted to the Strecker product (XXXIII-2) byreaction with an aldehyde D—CHO and KCN in analogy with the processreferred to in Scheme XXX. Compounds such as (XXXIII-2) may be condensedwith compounds such as (XXXI-2) followed by reduction to give compoundssuch as (XXXIII-3) (see for example Meyer et al. Synthesis, 2005, pp.945-956 and Meyer et al Synlett, 2003, pp 1427-1430). Compounds such as(XXXIII-3) may be deprotected using standard conditions for removal ofBoc and SEM groups (see General Procedure 23) and the resultant aminocompound reacted with an appropriate acid under conventional amide bondforming conditions to give compounds (XXXIII-4) wherein T, R_(D), and Dare as described herein.

Certain compounds of the invention may also be prepared using themethods shown generally in Scheme XXXIV. The ketone XXXIV-1 (Reference:US20090076076; p19, [0146]) can be homologated in two steps to thealdehyde XXXIV-3. In the first step, the ketone can be reacted withdimethylsulfonium methylide in dimethylsulfoxide to produce the epoxideXXXIV-2. The epoxide can be rearranged to the aldehyde by treatment withan acid such p-toluenesulfonic acid with heating in toluene attemperatures between around 80-110° C. (References: J. Am. Chem. Soc.(1965) 1353, 1358; J. Org. Chem. (1972) 4075, 4076, 4077; Bioorg. Med.Chem. Lett. (2009) 5684, 5686). The aldehyde XXXIV-3 can be converted tothe diol XXXIV-4 with potassium carbonate and formaldehyde in ethanol asdescribed generally in J. Am. Chem. Soc, 1951, 73, p5171 and U.S. Pat.No. 5,095,153, Example 3a. The diol can be converted to the bismesylateXXXIV-5 by reaction with excess methanesulfonyl chloride andtriethylamine in dichloromethane at 0° C. to room temperature. Thebismesylate can be converted to the azide XXXIV-6 by reaction withsodium azide (about 1 equivalent) in DMPU and heating up to around 110°C. The azide can be converted to the phosphorimidate XXXIV-7 by reactionwith freshly distilled triethylphosphite (about 1 equivalent) inanhydrous toluene/tetrahydrofuran at room temperature. Thephosphorimidate can be converted to the azetidine-phosphonate XXXIV-8 byheating in o-xylene up to around 150° C. The azetidine-phosphonate canbe converted to the azetidine XXXIV-9 by reaction with trifluoroaceticacid in dichloromethane at room temperature. The azetidine can bereacted with an appropriate aryl halide (e.g., iodide) using theBuchwald reaction to generate an N-arylazetidine XXXIV-10. Appropriateconditions include reaction with an aryliodide (about 2 equivalent),Pd₂(dba)₃ (about 0.025 equivalent),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos; about 0.1equivalents) and sodium tert-butoxide (about 1.2 equivalent) withheating in a solvent such as dioxane to 80-100° C., optionally withmicrowave irradiation. The bisbromide may be converted to thebisboronate XXXIV-11 by reaction with bis(pinacolato)diborane, potassiumacetate, and PdCl₂(dppf) in a solvent such as DME, dioxane, or DMSO withheating up to around 85° C. The bisboronate can be converted tocompounds of the invention XXXIV-12 by reaction with an appropriatehalide (i.e. Suzuki reaction) such asmethyl(S)-1-((S)-2-(5-bromo-1H-imidazol-2-yl)-pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate.

Certain compounds of the invention may also be prepared using themethods shown generally in Scheme XXXV. Compounds such as XXXV-1 can beprepared using known methods by alkylation of a malonate ester with abenzyl halide. Compound XXXV-1 can be converted to compound XXXV-2 byreduction with lithium aluminum hydride. Compound XXXV-2 can beconverted to compound XXXV-3 by reaction with Ms₂O and a base such asdiisopropylethylamine. Compound XXXV-3 may be converted to compoundXXXV-4 using methods analogs to those to convert XXXIV-5 to XXXIV-9 (seeScheme XXXIV). Similarly compound XXXV-4 may be converted to compoundXXXV-5 using a Buchwald reaction analogous to that of Scheme XXXIV.Compounds XXXV-5, in turn, may be converted to XXXV-6 by demethylation(e.g. with BBr₃) and triflate formation with Tf₂O. Compounds XXXV-6 maybe converted to compounds XXXV-7 by analogy with the conversion ofXXXIV-10 to XXXIV-11. Finally, compounds XXXV-7 may be converted tocompounds XXXV-8 using the Suzuki coupling of Scheme XXXIV.

In the foregoing Schemes (Schemes I-XXXV), compounds are shown whereinan aromatic ring (e.g., phenyl) is substituted with groups in aparticular regiochemistry (e.g., para). A starting material orintermediate with para-substitution provides a final product withpara-substitution in the foregoing Schemes. It is understood by one ofskill in the art that substitution in the foregoing Schemes of astarting material or intermediate with a different regiochemistry (e.g.,meta) would provide a final product with a different regiochemistry. Forexample, replacement of a para-substituted starting material orintermediate in the foregoing Schemes with a meta substituted startingmaterial or intermediate would lead to a meta-substituted product.

If a moiety described herein (e.g., —NH₂ or —OH) is not compatible withthe synthetic methods, the moiety may be protected with a suitableprotecting group that is stable to the reaction conditions used in themethods. The protecting group may be removed at a suitable point in thereaction sequence to provide a desired intermediate or target compound.Suitable protecting groups and methods for protecting or deprotectingmoieties are well know in the art, examples of which can be found inGreene and Wuts, supra. Optimum reaction conditions and reaction timesfor each individual step may vary depending on the particular reactantsemployed and substituents present in the reactants used. Solvents,temperatures and other reaction conditions may be readily selected byone of ordinary skill in the art based on the present invention.

Other compounds of the invention can be similarly prepared according tothe above-described schemes as well as the procedures described infollowing Intermediates, General Procedures, and Examples, asappreciated by those skilled in the art. It should be understood thatthe above-described embodiments and schemes and the followingIntermediates, General Procedures, and Examples are given by way ofillustration, not limitation. Various changes and modifications withinthe scope of the present invention will become apparent to those skilledin the art from the present description.

Example compounds below were named using ACD Name version 12 (ACD Namev12). Other compounds were named using ChemDraw version 9.0 (v9), unlessotherwise indicated as being named using ACD Name v12. Both namingprograms may provide a chemical name that depends on the tautomericstructure chosen for naming. Structures may be shown or named as anychemically distinct tautomer.

For example, the tautomeric structure:

is given the following names:

-   (S)-6,6′-((2R,5R)-1-phenylpyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole)    (Chemdraw v9);-   6,6′-[(2R,5R)-1-phenylpyrrolidine-2,5-diyl]bis{2-[(2S)-pyrrolidin-2-yl]-1H-benzimidazole}    (ACD Name v12).

The tautomeric structure:

is given the following names:

-   (S)-5,5′-((2R,5R)-1-phenylpyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole)    (Chemdraw v9);-   5,5′-[(2R,5R)-1-phenylpyrrolidine-2,5-diyl]bis{2-[(2S)-pyrrolidin-2-yl]-1H-benzimidazole}    (ACD Name v12).

The tautomeric structure:

is given the following names:

-   (S)-5,5′-((2R,5R)-1-phenylpyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole)    (Chemdraw v9);-   5-[(2R,5R)-1-phenyl-5-{2-[(2S)-pyrrolidin-2-yl]-1H-benzimidazol-6-yl}pyrrolidin-2-yl]-2-[(2S)-pyrrolidin-2-yl]-1H-benzimidazole    (ACD Name v12).

Certain compounds in the Examples below can be purified usingreverse-phase HPLC. Purification can be conducted using either a C18 orC8 reverse-phase column. Compounds can be eluted using a gradient ofabout 10-100% acetonitrile in 0.1% aqueous TFA; about 60-100% methanolin 10 mM aqueous ammonium acetate; or about 10-95% methanol in 10 mMaqueous ammonium acetate. For purifications conducted with TFA, theproduct thus obtained may be in the form of a TFA salt. Compounds may becharacterized as the TFA salt or as the free base followingneutralization, extraction and isolation.

Certain compounds in the Examples below can be purified using normalphase silica gel chromatography including traditional flashchromatography or an automated purification system (e.g., IscoCombi-Flash, Analogix Intelliflash) using pre-packed silica gel columns(55 or 35 μm silica gel, Isco gold columns). Compounds can also bepurified by prep-TLC.

Typical solvents for silica gel chromatography include: Ethyl acetate inhexanes, Diethyl ether in hexanes, THF in hexanes, Ethyl acetate inmethylene chloride, Methanol in methylene chloride, Methanol inmethylene chloride with NH₄OH, Acetone in hexanes, and Methylenechloride in hexanes.

Synthesis of Intermediates

Intermediate 1 (S)-tert-butyl2-(4-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate Intermediate 1A(S)-tert-butyl 2-formylpyrrolidine-1-carboxylate

To an oven-dried 500-mL 3-neck flask purged with nitrogen was addedoxalyl chloride (5.32 mL, 60.8 mmol) and anhydrous dichloromethane (125mL), and the solution was cooled to −78° C. A solution of anhydrous DMSO(7.30 mL, 103 mmol) in anhydrous dichloromethane (25 mL) was addeddropwise from a constant-pressure addition funnel over a 20-minuteperiod. A solution of (S)-tert-butyl2-(hydroxymethyl)pyrrolidine-1-carboxylate (9.41 g, 46.8 mmol) inanhydrous dichloromethane (50 mL) was added dropwise from aconstant-pressure addition funnel over a 20-minute period, and then thereaction mixture was stirred at −78° C. for 30 minutes. Triethylamine(32.6 mL, 234 mmol) was added dropwise via syringe over a 5-minuteperiod and the thick white mixture was stirred in an ice-water bath for30 minutes. The reaction was quenched with 10% (w/v) aq. citric acid (30mL). The mixture was partitioned in a separatory funnel between Et₂O(550 mL) and 10% (w/v) aq citric acid. The layers were separated, andthe organic phase was washed with water and brine. The organic phase wasdried over anhydrous Na₂SO₄, filtered, and concentrated to afford ayellow oil (9.4 g), which was used directly in the next reaction.

Intermediate 1B (S)-tert-butyl2-(1H-imidazol-2-yl)pyrrolidine-1-carboxylate

The product from Intermediate 1A (20 g, 100 mmol) was dissolved inmethanol (50.2 mL) and ammonium hydroxide (50.2 mL) was added. To thissolution glyoxal (40% in water; 24.08 mL, 211 mmol) was added, dropwise,over 10 minutes. The reaction was stirred at room temperature overnight.The reaction was concentrated under reduced pressure, diluted with 50 mLof water, and then extracted with ethyl acetate. The organic layer waswashed with brine, dried (Na₂SO₄) and concentrated to a tan solid. Thesolid was treated with ether and concentrated. The solid was thentriturated with 2:1 diethyl ether:hexanes (150 mL) to afford 17 g ofsolid, which was used directly in the next reaction. ¹HNMR (400 MHz,DMSO-d₆) δ ppm 1.14/1.40 (s, 9H), 1.81-2.12 (m, 4H), 3.32-3.33 (m, 1H),3.35-3.50 (m, 1H), 4.72-4.81 (m, 1H), 6.84 (s, 1H), 11.68 (s, 1H).

Intermediate 1C (S)-tert-butyl2-(4,5-dibromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

N-Bromosuccinimide (108 mmol) was added to a cold (0° C.) solution ofthe product from Intermediate 1B (12.05 g, 50.8 mmol) in dichloromethane(200 mL). The mixture was stirred in ice bath for 2 hours and thenconcentrated, dissolved in ethyl acetate (250 mL), washed with water(3×150 mL) and brine (1×100 mL), dried (MgSO₄), and concentrated to verydark residue. The residue was mixed with and concentrated fromdichloromethane/hexanes (1:1) to get brown solid (˜19 g). The solid wastriturated with ether (˜100 mL) and filtered to isolate a tan solid(13.23 g, 65% yield). ¹H NMR (400 MHz, CDCl₃) δ ppm 1.49 (s, 9H),1.86-2.17 (m, 3H), 2.80-2.95 (m, 1H), 3.30-3.44 (m, 2H), 4.85 (dd,J=7.54, 2.55 Hz, 1H), 10.82 (s, 1H); MS (DCI+) m/z 394/396/398 (M+H)⁺.

Intermediate 1D (S)-tert-butyl2-(4-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

The product from Intermediate 1C (6.25 g, 15.82 mmol) was dissolved indioxane (200 mL) and water (200 mL) in a 1 L round bottom flask equippedwith a condenser and glass stopper. A solution of sodium sulfite (22.38g, 174 mmol) in water (200 mL) was added, and the mixture was heated atreflux for 16 hours. The reaction mixture was cooled to roomtemperature, and dioxane and some water were removed by rotaryevaporation. The residue was extracted with dichloromethane. Thecombined organic phases were washed with brine (50 mL), dried overanhydrous Na₂SO₄, filtered, and concentrated by rotary evaporation,co-evaporating with 2:1 hexanes/dichloromethane (100 mL) to give a beigefoam (4.38 g). The foam was dissolved in dichloromethane (2 mL), hexanes(2 mL) were added, and the resultant solution was applied to a column,and purified by silica gel flash chromatography eluting with 30% to 80%ethyl acetate/hexanes to afford the title compound as a white solid(3.48 g). ¹H NMR (400 MHz, CDCl₃) δ ppm 1.48 (s, 9H), 1.83-2.33 (m, 3H),2.79-3.02 (m, 1H), 3.37 (dd, J=7.10, 5.37 Hz, 2H), 4.88 (dd, J=7.59,2.49 Hz, 1H), 6.92 (s, 1H), 10.70 (br s, 1H); MS (ESI+) m/z 316/318(M+H)⁺.

Intermediate 2 (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid

To (S)-2-amino-3-methylbutanoic acid (57 g, 487 mmol) dissolved indioxane (277 mL) was added a 2 N aqueous sodium hydroxide solution (803mL, 1606 mmol) followed by the dropwise addition of methyl chloroformate(75 mL, 973 mmol) over 1 hour which caused warming of the solution tooccur. After the addition, the mixture was heated at 60° C. for 22hours, then cooled and extracted with dichloromethane (400 mL). Theresultant aqueous layer was cooled in an ice bath, and then 12 Nhydrochloric acid was added dropwise until the pH was 2. The resultantmixture was stirred at 0° C. for 2 hours, and then the resultant solidwas collected by vacuum filtration, and dried in a vacuum oven toprovide 80 g (94%) of the title compound as a colorless solid. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 12.50 (bs, 1H), 7.34 (d, J=8.6 Hz, 1H), 3.84(dd, J=8.6, 6.0 Hz, 1H), 3.54 (s, 3H), 2.03 (m, 1H), 0.86 (t, J=7.0 Hz,6H).

Intermediate 3methyl(S)-1-((S)-2-carbamoylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamateIntermediate 3A (S)-pyrrolidine-2-carboxamide hydrochloride salt

To (S)-tert-butyl 2-carbamoylpyrrolidine-1-carboxylate (29.8 g, 139mmol) was added a solution of 4 N HCl in dioxane (209 mL, 836 mmol), andthe resultant mixture was stirred at room temperature for 18 hours. Themixture was then concentrated and triturated with diethyl ether thenvacuum filtered and dried under vacuum to provide 21.6 g (104%) of thetitle product as a colorless solid.

Intermediate 3Bmethyl(S)-1-((S)-2-carbamoylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

Intermediate 3A (21.6 g, 144 mmol), Intermediate 2 (29.1 g, 166 mmol),1H-benzo[d][1,2,3]triazol-1-ol hydrate (27.6 g, 180 mmol),N¹—((ethylimino)methylene)-N³, N³-dimethylpropane-1,3-diaminehydrochloride (34.6 g, 180 mmol) and 4-methylmorpholine (63.5 mL, 578mmol) were dissolved in dichloromethane (960 mL) and stirred at roomtemperature for 18 hours. The resultant solution was then concentratedto a residue, water was then added and the solution extracted with a 25%isopropanol in chloroform solution (2×2000 mL). The organic layer waswashed with brine, and then the organic extract was dried over MgSO₄,then concentrated to a yellow oil which was purified by columnchromatography eluting with a gradient of 0-10% methanol indichloromethane to provide 25 g (64%) of the title compound as acolorless solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.28 (m, 2H), 6.81 (s,1H), 4.24 (dd, J=8.1, 4.4 Hz, 1H), 4.00 (t, J=8.4 Hz, 1H), 3.75 (m, 1H),3.55 (m, 1H), 3.50 (s, 3H), 2.02 (m, 1H), 1.97 (m, 2H), 1.80 (m, 2H),0.92 (d, J=6.7 Hz, 3H), 0.86 (d, J=8.6 Hz, 3H).

Intermediate 4methyl(S)-1-((S)-2-(5-bromo-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamateIntermediate 4A (S)-5-bromo-2-(pyrrolidin-2-yl)-1H-imidazolehydrochloride

A mixture of Intermediate 1D (5.0 g, 15.8 mmol) in 4 M HCl/Dioxane (40mL) was allowed to stir for one hour. The mixture was concentrated toafford 3.99 g (100%) of the title compound. MS (ESI) m/z 217 (M+H)⁺.

Intermediate 4Bmethyl(S)-1-((S)-2-(5-bromo-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

A mixture of Intermediate 4A (3.99 g, 15.8 mmol), Intermediate 2 (2.77g, 15.8 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride (3.63 g, 19.0 mmol), 1-hydroxy-benzotriazole hydrate (2.90g, 19.0 mmol) and N-methylmorpholine (12.2 mL, 111.0 mmol) in DMF (150mL) were allowed to stir overnight. The mixture was diluted with H₂O andextracted with EtOAc (3×300 mL). The organic was washed with H₂O andbrine. The organic phase was then dried (MgSO₄), filtered andconcentrated. Purification by chromatography (silica gel, 75% EtOAc inhexanes) afforded 5.2 g (88%) of the title compound. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.79 (dd, J=6.67, 3.63 Hz, 6H), 1.84-1.96 (m, 3H),2.02-2.14 (m, 2H), 3.51 (s, 3H), 3.66-3.80 (m, 2 H), 3.96-4.03 (m, 1H),4.91-4.99 (m, 1H), 7.06 (d, J=1.52 Hz, 1H), 7.26 (d, J=8.46 Hz, 1H),12.01 (s, 1H); MS (ESI) m/z 373 (M+H)⁺.

Intermediate 5 (1S,4S)-1,4-bis(4-chloro-3-nitrophenyl)butane-1,4-diyldimethanesulfonate Intermediate 5A2-bromo-1-(4-chloro-3-nitrophenyl)ethanone Method A:

To a flask equipped with a magnetic stir bar and under an atmosphere ofN₂ was added 4′-chloro-3′-nitroacetophenone (10.0 g, 50.1 mmol) and THF(100 mL). To this stirring mixture was added portion-wisephenyltrimethylammonium tribromide (19.78 g, 52.6 mmol) over a 15minutes time period. The resultant mixture was then stirred withmonitoring every hour via LCMS. After 3 hours, the mixture was thenfiltered and resulting solids washed with EtOAc. The organic solutionwas then concentrated, H₂O and 10% aq. NaHCO₃ were added, and themixture was washed with EtOAc (2×300 mL). The combined organic layerswere then washed with brine, dried (MgSO₄), filtered and concentrated.The residue material was then subjected to purification viacrystallization. The residue was dissolved in EtOAc (100 mL) and hexaneswere slowly added until the mixture was cloudy. After standing for a fewhours, 2-bromo-1-(4-chloro-3-nitrophenyl)ethanone (9.81 g, 70%) wascollected as an off white colored solid product. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 5.00 (s, 2 H) 7.98 (d, J=8.54 Hz, 1H) 8.24 (dd, J=8.54,2.14 Hz, 1H) 8.61 (d, J=1.98 Hz, 1H).

Method B:

In a 500 mL round-bottomed flask was added1-(4-chloro-3-nitrophenyl)ethanone (11.98 g, 60 mmol) in benzene (75 mL)to give a white suspension. Bromine (9.59 g, 60.0 mmol) was addeddropwise over 5 minutes to give a deep red solution. The mixture wasstirred for 1 hour to give a yellow solution that was concentrated invacuo to a yellow solid. Recrystallized from 9:1 hexane/ethyl acetategave 2-bromo-1-(4-chloro-3-nitrophenyl)ethanone as yellow needles.

Intermediate 5B 1,4-bis(4-chloro-3-nitrophenyl)butane-1,4-dione

Zinc (II) chloride (14.68 g, 108 mmol) was added to toluene (81 mL)followed by diethylamine (8.35 mL, 81 mmol) and tert-butanol (7.73 mL,81 mmol). The resultant heterogeneous solution was stirred at roomtemperature for approximately 2 hours. Afterwards Intermediate 5A (15.0g, 53.9 mmol) and 4′-chloro-3′-nitroacetophenone (16.13 g, 81 mmol) wereadded to the solution in one portion, and the resultant mixture wasstirred at room temperature for 42 hours. The reaction was then quenchedwith 5% aqueous sulfuric acid (500 mL) and stirred vigorously to inducesolid formation. The resultant solid was collected by vacuum filtration,then washed with toluene, water, and methanol successively. Then thesolid was added to a solution of hot ethyl acetate and resultingheterogeneous solution was stirred for 30 minutes. The solid was thencollected and dried overnight in a vacuum oven to provide 16.6 g (78%)of the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ 8.61 (d, J=1.9 Hz,2H), 8.27 (dd, J=8.4, 1.9 Hz, 2H), 7.96 (d, J=8.3 Hz, 2H), 3.48 (s, 4H).

Intermediate 5C (1S,4S)-1,4-bis(4-chloro-3-nitrophenyl)butane-1,4-diol

(R)-(+)-α,α-Diphenyl-2-pyrrolidinemethanol (1.08 g, 4.28 mmol) wasdissolved in 70 mL of THF at ambient temperature in a dry flask undernitrogen and trimethyl borate (650 uL, 5.54 mmol) was added dropwise.The resulting solution was stirred for 1 hour. The solution was cooledin a cold bath to −10° C. and the N,N-diethylaniline borane (9.18 mL,51.6 mmol) was added dropwise with some bubbling. After 15 minutes, thissolution was transferred to an addition funnel and added dropwise to1,4-bis(4-chloro-3-nitrophenyl)butane-1,4-dione (Intermediate 5B) (10.0g, 25.2 mmol) suspended in 200 mL of THF and cooled to −10° C. Bubblingwas observed. After the addition, the mixture was stirred at ambienttemperature for 4 hours. The mixture was cooled in an ice bath and 30 mLor methanol was added dropwise until bubbling stopped, then the mixturewas allowed to stir at ambient temperature for 30 minutes. The mixturewas filtered to get rid of a trace of insoluble unreacted startingmaterial. The filtrate was concentrated, poured into 1 M HCl andextracted into ethyl acetate, dried over sodium sulfate, andconcentrated to give the title compound (9.9 g, 99%) as a yellow waxysolid. Chiral HPLC e.e. >99.9% (RR diol was undetectable). ¹H NMR (400MHz, DMSO-d₆) δ ppm 7.94 (d, J=1.9 Hz, 2H), 7.69 (d, J=8.4 Hz, 2H), 7.60(dd, J=8.4, 1.9 Hz, 2H), 4.65 (m, 2H), 1.62 (m, 4H).

Intermediate 5D (1S,4S)-1,4-bis(4-chloro-3-nitrophenyl)butane-1,4-diyldimethanesulfonate

In a 1 L round-bottomed flask containing Intermediate 5C (20.0 g, 49.9mmol) was added 310 mL of dichloromethane with stirring and cooling inan ice bath. To the slurry was added triethylamine (20.84 mL, 150 mmol)and after 10 minutes stirring in the ice bath, a solution ofmethanesulfonyl chloride (8.5 mL, 110 mmol) in dichloromethane (10 mL)was added dropwise to the reaction. After complete addition, the flaskwas removed from the ice bath and stirred at room temperature for 3hours. To the reaction was added water (400 mL) with vigorous stirringfor 20 minutes. The solid was collected by filtration and washedthoroughly with water dichloromethane and diethyl ether. The solid wasdried overnight in a vacuum drying oven at 60° C. to provide a whitesolid (20.49 g, 73.7% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.81-1.91(m, 2H) 2.06 (m, 2 H) 3.18 (s, 6H) 5.73-5.84 (m, 2H) 7.71-7.77 (m, 2H)7.80-7.85 (m, 2H) 8.13 (d, J=1.74 Hz, 2H).

Intermediate 5.1 (1R,4R)-1,4-bis(4-chloro-3-nitrophenyl)butane-1,4-diol

(1R,4R)-1,4-bis(4-chloro-3-nitrophenyl)butane-1,4-diol can be preparedusing (S)-(−)-α,α-diphenyl-2-pyrrolidinemethanol and the method ofIntermediate 5C.

Intermediate 5.2 (1R,4R)-1,4-bis(4-chloro-3-nitrophenyl)butane-1,4-diyldimethanesulfonate

(1R,4R)-1,4-bis(4-chloro-3-nitrophenyl)butane-1,4-diol can betransformed to (1R,4R)-1,4-bis(4-chloro-3-nitrophenyl)butane-1,4-diyldimethanesulfonate as described under Intermediate 5D.

Intermediate 6 (1R,4R)-1,4-bis(4-nitrophenyl)butane-1,4-diyldimethanesulfonate Intermediate 6A1,4-Bis(4-nitrophenyl)butane-1,4-dione

Anhydrous zinc(II)chloride (2.73 g, 20.00 mmol) was stirred in drybenzene (15 mL) while diethylamine (1.558 mL, 15.00 mmol) and t-butanol(1.435 mL, 15.00 mmol) were added, and the resulting mixture was stirredat room temperature for 90 minutes to give a cloudy solution. To thismixture was added 2-bromo-1-(4-nitrophenyl)ethanone (2.44 g, 10.00 mmol)and 1-(4-nitrophenyl)ethanone (2.477 g, 15.00 mmol), and the resultingmixture was stirred at room temperature overnight. The mixture waspoured into water (50 mL) and extracted with ethyl acetate (3×50 mL).The combined organic layers were dried over Na₂SO₄, filtered andconcentrated. The resulting residue was triturated with dichloromethaneto give an orange solid that was collected by filtration and dried togive the title compound (2.0 g, 61% yield).

Intermediate 6B (1R,4R)-1,4-bis(4-nitrophenyl)butane-1,4-diol

To (S)-(−)-α,α-diphenyl-2-pyrrolidinemethanol (2.71 g, 10.70 mmol) wasadded THF (80 mL) at 23° C. The very thin suspension was treated withtrimethyl borate (1.44 g, 13.86 mmol) over 30 seconds, and the resultingsolution was mixed at 23° C. for 1 hour. The solution was cooled to16-19° C., and N,N-diethylaniline borane (21.45 g, 132 mmol) was addeddropwise via syringe over 3-5 minutes (caution: vigorous H₂ evolution),while the internal temperature was maintained at 16-19° C. After 15minutes, the H₂ evolution had ceased. To a separate vessel was added theproduct from Example 6A (22.04 g, 95 wt %, 63.8 mmol), followed by THF(80 mL), to form an orange slurry. After cooling the slurry to 11° C.,the borane solution was transferred via cannula into the dione slurryover 3-5 minutes. During this period, the internal temperature of theslurry rose to 16° C. After the addition was complete, the reaction wasmaintained at 20-27° C. for an additional 2.5 hours. After reactioncompletion, the mixture was cooled to 5° C. and methanol (16.7 g, 521mmol) was added dropwise over 5-10 minutes, maintaining an internaltemperature <20° C. (note: vigorous H₂ evolution). After the exothermhad ceased (ca. 10 minutes), the temperature was adjusted to 23° C., andthe reaction was mixed until complete dissolution of the solids hadoccurred. Ethyl acetate (300 mL) and 1 M HCl (120 mL) were added, andthe phases were separated. The organic phase was then washedsuccessively with 1 M HCl (2×120 mL), H₂O (65 mL), and 10% aq. NaCl (65mL). The organics were dried over MgSO₄, filtered, and concentrated invacuo. Crystallization of the product occurred during the concentration.The slurry was warmed to 50° C., and heptane (250 mL) was added over 15minutes. The slurry was then allowed to mix at 23° C. for 30 minutes andfiltered. The wet cake was washed with 3:1 heptane:ethyl acetate (75mL), and the orange, crystalline solids were dried at 45° C. for 24hours to provide the title compound (15.35 g, 99.3% ee, 61% yield),which was contaminated with 11% of the meso isomer (vs. dl isomer).

Intermediate 6C (1R,4R)-1,4-bis(4-nitrophenyl)butane-1,4-diyldimethanesulfonate

The product from Intermediate 6B (5.01 g, 13.39 mmol) was combined with2-methyltetrahydrofuran (70 mL) and cooled to −5° C., andN,N-diisopropylethylamine (6.81 g, 52.7 mmol) was added over 30 seconds.Separately, a solution of methanesulfonic anhydride (6.01 g, 34.5 mmol)in 2-methyltetrahydrofuran (30 mL) was prepared and added to the diolslurry over 3 minutes, maintaining the internal temperature between −15°C. and −25° C. After mixing for 5 minutes at −15° C., the cooling bathwas removed and the reaction was allowed to warm slowly to 23° C. andmixed for 30 minutes. After reaction completion, the crude slurry isused directly without purification or isolation.

Intermediate 7 ((1R,4R)-1,4-bis(4-bromophenyl)butane-1,4-diyldimethanesulfonate Intermediate 7A1,4-bis(4-bromophenyl)butane-1,4-dione

To a solution of zinc(II) chloride (19.62 g, 144 mmol) in benzene (108mL) were added diethylamine (11.16 mL, 108 mmol) and 2-methylpropan-2-ol(10.32 mL, 108 mmol) and the mixture was stirred at room temperature for2 hours. 2-Bromo-1-(4-bromophenyl)ethanone (20.0 g, (72 mmol) and1-(4-bromophenyl)ethanone (21.48 g, 108 mmol) were added in one portion,and the mixture was stirred overnight (18 hours). The reaction mixturewas quenched with 5% H₂SO₄ (500 mL) and stirred vigorously to induceprecipitation of the product, which was collected by vacuum filtrationand washed with benzene, water, methanol, and then dichloromethane,successively. The product was dried under vacuum to give the titlecompound as a white solid (11.15 g, 39.1% yield).

Intermediate 7B (1R,4R)-1,4-bis(4-bromophenyl)butane-1,4-diol

To (S)-(−)-α,α-diphenyl-2-pyrrolidinemethanol (3.81 g, 15.04 mmol) wasadded THF (140 mL) at 23° C. The thin slurry was treated with trimethylborate (2.189 mL, 19.63 mmol) to form a clear solution. After stirringfor 1.5 hours, the solution was cooled to 10-15° C., andN,N-diethylaniline borane (33.1 mL, 186 mmol) was added over 5-10minutes via a syringe. A slight exotherm and H₂ evolution were observed.To a separate vessel was charged Intermediate 7A (35.045 g, 88 mmol),followed by THF (140 mL), to form a slurry. The slurry was cooled to 10°C. The cooled borane solution was transferred via cannula into the dioneslurry over approximately 5 minutes, maintaining the internaltemperature <25° C. After the transfer was complete, the slurry was heldat 15° C. for 5 minutes and then the temperature was maintained at 23°C. for 3 hours. After reaction completion, the solution was cooled to 5°C., and methanol (31.6 mL, 780 mmol) was added slowly to maintain atemperature <20° C. (note: vigorous evolution of hydrogen). The hazysolution was mixed for an additional 1 hour in order to ensure completequenching. The hazy solution was diluted with EtOAc (500 mL) and 1 M HCl(220 mL). The phases were separated, and the organic phase was washedsuccessively with 1 M HCl (2×220 mL), H₂O (110 mL), and 25% aq. NaCl(110 mL). The organic layer was concentrated in vacuo; then the residuewas dissolved in EtOAc, filtered, concentrated and crystallized fromEtOAc/hexane to provide the title compound (16.92 g; 100% ee; 47%isolated yield).

Intermediate 7C (1R,4R)-1,4-bis(4-bromophenyl)butane-1,4-diyldimethanesulfonate

To Intermediate 7B (0.60 g, 1.500 mmol) in anhydrous CH₂Cl₂ (15 mL) at0° C. was added Et₃N (0.627 mL, 4.50 mmol), and the resulting mixturewas stirred at 0° C. for 10 minutes until a homogenous solution wasobtained. To the cooled solution was added methanesulfonyl chloride(0.292 mL, 3.75 mmol) dropwise, and the resulting mixture was stirred at0° C. for 1.5 hours until the reaction was complete as determined by TLC(1:1 EtOAc:hexanes). Solvent was removed in vacuo to give a solid, whichwas dried in vacuo.

Intermediate 8(2S,4S)-1-(tert-butoxycarbonyl)-4-(tert-butyldimethylsilyloxy)pyrrolidine-2-carboxylicacid

(2S,4S)-1-(tert-Butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid(5.31 g, 22.96 mmol) and imidazole (7.82 g, 115 mmol) were combined indichloromethane (106 mL) and dimethylformamide (22 mL) at ambienttemperature and treated with portionwise addition oftert-butylchlorodimethylsilane (7.61 g, 50.5 mmol). The mixture wasstirred for 18 hours then diluted with water and extracted into ethylacetate and concentrated to provide the title compound.

Intermediate 9(S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidine-2-carboxylicacid

Intermediate 2 (150 g, 856 mmol), HOBt hydrate (138 g, 899 mmol) and DMF(1500 mL) were charged to a flask. The mixture was stirred for 15minutes to give a clear solution. EDC hydrochloride (172 g, 899 mmol)was charged and mixed for 20 minutes. The mixture was cooled to 13° C.and (L)-proline benzyl ester hydrochloride (207 g, 856 mmol) charged.Triethylamine (109 g, 1079 mmol) was then charged in 30 minutes. Theresulting suspension was mixed at room temperature for 1.5 hours. Thereaction mixture was cooled to 15° C. and 1500 mL of 6.7% NaHCO₃ chargedin 1.5 hours, followed by the addition of 1200 mL of water over 60minutes. The mixture was stirred at room temperature for 30 minutes, anthen it was filtered and washed with water/DMF mixture (1:2, 250 mL) andthen with water (1500 mL). The wet cake was dried at 55° C. for 24 hoursto give 282 g of product (S)-benzyl1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidine-2-carboxylateas a white solid (90%).

(S)-Benzyl1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidine-2-carboxylate(40 g) and 5% Pd/Alumina were charged to a Parr reactor followed by THF(160 mL). The reactor was sealed and purged with nitrogen (6×20 psig)followed by a hydrogen purge (6×30 psig). The reactor was pressurized to30 psig with hydrogen and agitated at room temperature for approximately15 hours. The resulting slurry was filtered through a GF/F filter andconcentrated to approximately 135 g solution. Heptane (120 mL) wasadded, and the solution was stirred until solids formed. After anaddition 2-3 hours, additional heptane (240 mL) was added drop-wise, theslurry was stirred for approximately 1 hour, then filtered. The solidswere dried to afford the title compound(S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidine-2-carboxylicacid.

Intermediate 10 4-Cyclohexyl-3-fluoroaniline hydrochloride Intermediate10A 3-Fluoro-4-iodoaniline

To a suspension of 3-fluoroaniline (1.0 mL, 1.16 g, 10.39 mmol) andsolid sodium bicarbonate (1.75 g, 20.79 mmol) in 1:1methanol-dichloromethane (20 mL) at 0° C. was added a solution of benzyltrimethylammonium dichloroiodate (3.62 g, 10.39 mmol) in dichloromethane(15 mL) over 30 minutes. The mixture was then allowed to warm to roomtemperature for 1 hour. The mixture was quenched by addition of waterand the organic layer was extracted with water (2×). Drying (Na₂SO₄) andconcentration in vacuo afforded an oil, which was chromatographed over a100 g silica gel cartridge, eluting with 10-100% ethyl acetate inhexanes. These procedures afforded the title compound (2.20 g, 89%) as apink solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.41 (dd, J=8.3, 7.3 Hz, 1H),6.42 (dd, J=9.9, 2.5 Hz, 1H), 6.27 (dd, J=8.5, 2.5 Hz; 1H), 3.81 (s,2H); MS+ESI m/z (rel abundance) 238 (100, M+H).

Intermediate 10B 4-(Cyclohexen-1-yl)-3-fluoroaniline

The procedure to prepare the title compound is described in GeneralProcedure 1.2A.

Intermediate 10C 4-Cyclohexyl-3-fluoroaniline hydrochloride

A solution of 4-(cyclohexen-1-yl)-3-fluoroaniline (General Procedure1.2A) (1.16 g, 6.07 mmol) in ethanol (30 mL) was treated with 10%palladium on carbon (300 mg) followed by hydrogenation at one atmospherefor 18 hours. The mixture was filtered through diatomaceous earth andconcentrated to about one quarter volume and treated with a solution ofhydrogen chloride in dioxane (4 N, 10 mL). The mixture was thenpartially concentrated in vacuo to about one quarter volume and dilutedwith ether (ca. 100 mL) and the solids were collected by filtration.After drying in a vacuum oven at 50° C. for 3 hours, these proceduresafforded the title compound (1.13 g, 81%) as a light grey solid. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 7.35 (t, J=8.1 Hz, 1H), 7.03 (d, J=9.4 Hz, 2H),2.76 (dd, J=15.6, 6.9 Hz, 1H), 1.74 (m, 5H), 1.40 (m, 4H), 1.21 (m, 1H).MS (DCI+) m/z (rel abundance) 194 (100, M+H), 211 (67, M+NH₄).

Intermediate 11AN-(4-bromo-5-fluoro-2-nitrophenyl)-2,2,2-trifluoroacetamide

To a flask containing trifluoroacetic anhydride (10.0 mL, 70.5 mmol) at0° C. was added 4-bromo-3-fluoroaniline (2.0 μg, 10.5 mmol) and stirringwas continued for 30 minutes (Charifson, P. S.; et al. J. Med. Chem.2008, 51, 5243-5263). Potassium nitrate (1.3 g, 12.6 mmol) was added andthe solution was allowed to warm to 25° C. The solution wasconcentrated, the residue dissolved in EtOAc and washed with 10% NaHCO₃,brine, dried (Na₂SO₄), and filtered. The filtrate was concentrated togive the title compound (3.5 g, 10.5 mmol, 100%).

Intermediate 11B 4-bromo-5-fluoro-2-nitroaniline

To N-(4-bromo-5-fluoro-2-nitrophenyl)-2,2,2-trifluoroacetamide (3.5 g,10.5 mmol) was added CH₃OH (30 mL) followed by 1.0 M K₂CO₃ (10.5 mL,10.5 mmol), and the solution was stirred for 30 minutes (Charifson, P.S.; et al. J. Med. Chem. 2008, 51, 5243-5263). The solution was dilutedwith H₂O and stirred for 1 hour. The resulting orange solid wascollected by filtration and dried in a vacuum oven to give the titlecompound (2.1, g, 8.8 mmol, 84%).

Intermediate 11C 4-bromo-5-fluorobenzene-1,2-diamine

To a solution of 4-bromo-5-fluoro-2-nitroaniline (1.0 g, 4.3 mmol) inTHF (9.0 mL), EtOH (9.0 mL) and H₂O (3 mL) was added iron powder (1.2 g,21.3 mmol) and ammonium chloride (0.34 g, 6.4 mmol), and the mixture washeated at 95° C. for 4 hours. The cooled mixture was diluted with EtOH,filtered through diatomaceous earth until no further color came throughthe filter, and concentrated. The residue was dissolved in EtOAc, washedwith H₂O, brine, dried (Na₂SO₄), filtered and concentrated. Hexane wasadded and the resulting solid collected by filtration to give the titlecompound (710 mg, 3.5 mmol, 81%).

Intermediate 12 4-bromo-3-chlorobenzene-1,2-diamine Intermediate 12A4-bromo-3-chloro-2-nitroaniline

3-Chloro-2-nitroaniline (5.00 g, 29.0 mmol) was dissolved in glacialacetic Acid (258 mL). N-Bromosuccinimide (5.06 g, 28.4 mmol) was addedand the resulting mixture was refluxed for 1 hour. The reaction wascooled to room temperature and poured into water to give a precipitatethat was filtered, rinsed with water and dried to constant weight togive the title compound (4.78 g, 67%). ¹H NMR (400 MHz, CDCL₃) δ ppm7.46 (d, J=9.0, 1H), 6.64 (d, J=9.0, 1H), 4.74 (s, 2H).

Intermediate 12B 4-bromo-3-chlorobenzene-1,2-diamine

4-Bromo-3-chloro-2-nitroaniline (4.78 g, 19.01 mmol) was dissolved inethanol (112 mL). Tin (II) chloride (14.42 g, 76 mmol) was added, andthe resulting mixture was stirred at reflux for 12 hours. The mixturewas cooled to room temperature, poured into water, and adjusted to pH 5with saturated sodium bicarbonate solution. The resulting solid wasfiltered and rinsed well with ethyl acetate. The filtrate was washedwith water and brine, dried over Na₂SO₄, filtered and concentrated invacuo. The crude product was purified by column chromatography on silicagel using a solvent gradient of 0-50% EtOAc in hexane to give the titlecompound (3.32 g, 79%). ¹H NMR (400 MHz, CDCl₃) δ ppm 6.94 (d, 1H), 6.51(d, J=7.0, 1H), 3.87 (br s, 2H), 3.46 (br s, 2H).

Intermediate 13 4-bromo-3-methylbenzene-1,2-diamine Intermediate 13AN-(3-bromo-2-methyl-6-nitrophenyl)-2,2,2-trifluoroacetamide

To a solution of 3-bromo-2-methylaniline (1.0 g, 5.37 mmol) in CH₂Cl₂(4.0 mL) at 0° C. was added trifluoroacetic anhydride (2.0 mL, 14.2mmol). The mixture was stirred at 0° C. for 30 minutes, and solidpotassium nitrate (0.679 g, 6.72 mmol) was added. The cooling bath wasremoved, and the mixture was stirred at room temperature overnight. LCMSshowed a single product formed. The mixture was concentrated in vacuo,and the residue was partitioned between water and CH₂Cl₂ (2×).

The organic layers were combined and dried over Na₂SO₄. The drying agentwas filtered off and the crude product was purified by crystallizationfrom aq EtOH to give the title compound (1.3 g, 74%).

Intermediate 13B 3-bromo-2-methyl-6-nitroaniline

A solution ofN-(3-bromo-2-methyl-6-nitrophenyl)-2,2,2-trifluoroacetamide (1.3 g, 3.97mmol) in CH₃OH (30 mL) was treated with potassium carbonate (1.099 g,7.95 mmol), and the mixture was stirred at 50° C. overnight. The mixturewas cooled to room temperature and poured into water, 1N aq HCl wasadded to adjust to pH 6, and the mixture was extracted with CH₂Cl₂ (3×).The combined extracts were dried over Na₂SO₄, and the drying agent wasfiltered off and solvent was removed in vacuo to give the title compoundas a yellow solid (0.57 g, 62%).

Intermediate 13C 4-bromo-3-methylbenzene-1,2-diamine

To a solution of 3-bromo-2-methyl-6-nitroaniline (0.45 g, 1.95 mmol) inEtOH (6 mL) was added tin(II) chloride (1.48 g, 7.8 mmol), and theresulting solution was stirred at 70° C. for 4 hours. The mixture wascooled to room temperature and poured into water, and 1 N aq. NaOH wasadded to adjust to pH>7. The resulting mixture was extracted with CH₂Cl₂(2×), and the combined extracts were dried over Na₂SO₄. The drying agentwas filtered off and solvent was removed in vacuo to give the titlecompound as an oil (0.34 g, 88%).

Intermediate 14 5-bromo-3-fluorobenzene-1,2-diamine

To a solution of 4-bromo-2-fluoro-6-nitroaniline (0.5 g, 2.1 mmol) inTHF (4.6 mL), EtOH (4.6 mL) and H₂O (1.5 mL) was added iron powder (0.6g, 10.6 mmol) and ammonium chloride (0.17 g, 3.2 mmol). The resultingmixture was stirred at 95° C. for 22 hours. The mixture was cooled toroom temperature and filtered through diatomaceous earth. The solid waswashed with EtOH until no further color came through the filter. Thefiltrate was concentrated and the residue was dissolved in EtOAc, washedwith H₂O and brine, dried over Na₂SO₄, filtered and concentrated to givethe title compound (0.43 g, 99%) as a brown, waxy solid.

Intermediate 15 4-bromo-3-fluorobenzene-1,2-diamine Intermediate 15A3-fluoro-2-nitroaniline

To a pressure tube was added 1,3-difluoro-2-nitrobenzene (2.8 mL, 26.4mmol) and 7 N NH₃ in CH₃OH (10 mL, 70 mmol). The tube was sealed and themixture was stirred at room temperature for 5 days. The solution wasdiluted with H₂O, extracted with CH₂Cl₂, and the combined extracts werewashed with brine, dried over Na₂SO₄, filtered and concentrated to givean oil. The oil was triturated with hexane and the resulting orangesolid was collected by filtration to give the title compound (2.1 g,51%).

Intermediate 15B 4-bromo-3-fluoro-2-nitroaniline

To a solution of 3-fluoro-2-nitroaniline (2.1 g, 13.4 mmol) in DMF (30mL) at 0° C. was added a solution of N-bromosuccinimide (2.4 g, 13.4mmol) in DMF (20 mL). The resulting solution was stirred at 0° C. for 30minutes and then warmed to room temperature over 1 hour. The solutionwas diluted with EtOAc, washed with H₂O and brine, dried over MgSO₄,filtered and concentrated to give the title compound (3.1 g, 97%).

Intermediate 15C 4-bromo-3-fluorobenzene-1,2-diamine

To a solution of 4-bromo-3-fluoro-2-nitroaniline (3.0 g, 12.8 mmol) inTHF (30 mL) was added EtOH (30 mL) and H₂O (10 mL) followed by ironpowder (3.6 g, 63.8 mmol) and ammonium chloride (1.0 g, 19.2 mmol). Theresulting mixture was stirred at 80° C. for 16 hours. The mixture wascooled to room temperature and filtered through diatomaceous earth. Thesolid was washed with EtOH until no further color came through thefilter. The filtrate was concentrated in vacuo and the crude product waspurified by column chromatography on silica gel using a solvent gradientof 0-40% EtOAc in hexane to give the title compound (2.2 g, 84%).

Intermediate 16 4-cyclopropyl-2-fluoroaniline

4-Cyclopropyl-2-fluoro-1-nitrobenzene (prepared as described in GeneralProcedure 1.2C) (2.2 g, 12.14 mmol) was dissolved in 7 mL of anethanol:THF:water 3:3:1 (v/v) mixture. To this was added ammoniumchloride (1.02 g, 19.07 mmol) followed by iron powder (3.50 g, 62.7mmol). The resulting mixture was heated in a 90° C. oil bath under anitrogen atmosphere with rapid stirring for one hour. The reactionmixture was vacuum filtered through a sand and diatomaceous earth plug.The filtrate was concentrated in vacuo and the residue partitionedbetween dichloromethane and water. The organic phase was washed withbrine, dried (MgSO₄) and concentrated in vacuo to provide an orange oil(1.90 g).

Intermediate 17 2-(methoxycarbonylamino)-3-methylbut-2-enoic acid

Intermediate 17A ethyl 2-(methoxycarbonylamino)-3-methylbut-2-enoate

A benzene solution (90 mL) of ethyl-3-methyl-2-oxobutanoate (4.03 g,28.0 mmol), methyl carbamate (2.098 g, 28.0 mmol) and pyridine4-methylbenzenesulfonate (0.70 g, 2.80 mmol) was heated to reflux in around bottom flask equipped with a Dean-Stark trap and reflux condenser.After 44 hours of heating the mixture was cooled and then partitionedbetween ethyl acetate (50 mL) and brine (50 mL). The organic phase waswashed with brine (2×50 mL) then dried (MgSO₄) and concentrated invacuo. The crude product was purified by chromatography on silica gel(ethyl acetate-hexanes) to provide the title compound as an off whitecrystalline solid (1.487 g, 26%).

Intermediate 17B 2-(methoxycarbonylamino)-3-methylbut-2-enoic acid

The product from Intermediate 17A (0.373 g, 1.85 mmol) was dissolved in2 mL of a 1:1(v/v) ethanol:water mixture at room temperature. To thiswas added lithium hydroxide (0.095 g, 3.99 mmol) in one portion. Afterstirring overnight, the reaction mixture was partitioned between ethylacetate (25 mL) and 1 N HCl (5 mL) to which was added solid NaCl. Theaqueous phase was extracted with ethyl acetate one time and the combinedorganics washed with brine (3×5 mL) then dried (MgSO₄) and concentratedto give the title compound (0.289 g, 90%) as an off white solidsufficiently pure for use as isolated.

Intermediate 18 (2S,3aS,6aS)-tert-butyl2-carbamoylhexahydrocyclopenta[b]pyrrole-1(2H)-carboxylate

Intermediate 18A (2S,3aS,6baS)-2-benzyl 1-tert-butylhexahydrocyclopenta[b]pyrrole-1,2(2H)-dicarboxylate

To a suspension of (2S,3aS,6aS)-benzyloctahydrocyclopenta[b]pyrrole-2-carboxylate hydrochloride (2.0 g, 7.10mmol) in dichloromethane (36 mL) at room temperature was addeddi-tert-butyl dicarbonate (1.70 g, 7.81 mmol) followed by triethylamine(2.18 mL, 15.62 mmol). The solution rapidly becomes homogeneous alongwith vigorous gas evolution which quickly subsides. After two hours, themixture was diluted with dichloromethane, washed with brine (3×60 mL),dried (MgSO₄) and concentrated. The crude product was purified bychromatography on silica gel (ethyl acetate-hexanes) to give the titlecompound (2.58 g, quantitative) as a clear oil.

Intermediate 18B(2S,3aS,6aS)-1-(tert-butoxycarbonyl)octahydrocyclopenta[b]pyrrole-2-carboxylicacid

The product from Intermediate 18A (2.45 g, 7.1 mmol) was dissolved inmethanol (35 mL) at room temperature. To this was added Pearlman'scatalyst (0.153 g) followed by vacuum degassing (3×) and hydrogenaddition (balloon). After one hour, the reaction mixture was vacuumfiltered through diatomaceous earth and the filtrate concentrated togive a clear thick oil (1.89 g, quantitative) which was sufficientlypure for use as isolated.

Intermediate 18C (2S,3aS,6aS)-tert-butyl2-carbamoylhexahydrocyclopenta[b]pyrrole-1(2H)-carboxylate

The product from Intermediate 18B (1.81 g, 7.1 mmol) was dissolved inTHF (40 mL) at room temperature under nitrogen. To this was addedN-methyl morpholine (1.0 mL, 9.09 mmol) and the resulting solution wascooled to −15° C. To the cold solution was added isobutylchloroformate(1.03 mL, 7.81 mmol) dropwise via syringe. A white precipitate forms atonce. On completion of the addition, the mixture was allowed to stir inthe cold for twenty minutes. Ammonia gas was then introduced by bubblingthrough the mixture for two minutes with additional cooling. Oncompletion of the addition, the reaction was allowed to warm to ice bathtemperature and stir for one half hour and then warmed to roomtemperature. After fifteen minutes at room temperature, the mixture waspoured into brine (450 mL) and extracted with dichloromethane (6×50 mL).The combined extracts were dried (MgSO₄) and concentrated. The crudeproduct was purified by chromatography on silica gel (ethylacetate-hexanes) to give the title compound (1.68 g, 93%) as a stickywhite foam.

Intermediate 19 (S,E)-tert-butyl2-(5-(3-oxoprop-1-enyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylateIntermediate 19A (S,E)-tert-butyl2-(5-(3-ethoxy-3-oxoprop-1-enyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate

To (S)-tert-butyl2-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate(2.973 g, 5.99 mmol), ethyl acrylate (0.714 mL, 6.59 mmol),tri-tert-butylphosphonium tetrafluoroborate (0.104 g, 0.359 mmol),N,N-dicyclohexylmethylamine (1.461 mL, 6.89 mmol), andtris(dibenzylideneacetone)dipalladium(0) (0.164 g, 0.18 mmol) dissolvedin THF (18 mL) had nitrogen bubbled through the solution for 15 minutesto remove the oxygen, and then the mixture heated at 60° C. for 2 hours.After cooling to room temperature the solution was filtered throughdiatomaceous earth and washed with EtOAc. The filtrated was thenconcentrated to a residue, and then the residue was dissolved indichloromethane and extracted with water. The organic layer was thendried and concentrated. The residue was purified by chromatography(silica gel, hexanes in ethyl acetate) which afforded 2.56 g, (83%) ofthe title compound. MS (ESI) m/z 516 (M+H)⁺.

Intermediate 19B (S,E)-tert-butyl2-(5-(3-hydroxyprop-1-enyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate

Intermediate 19A (2.56 g, 4.97 mmol) was dissolved in THF (17 mL), andthe mixture was cooled to −78° C. in a dry ice acetone bath. Then asolution of diisobutylaluminum hydride (1.0 N in THF, 22.75 mL, 24.75mmol) was added dropwise. The resultant mixture was allowed to slowlywarm to room temperature overnight, and then was quenched with a 1 Naqueous sodium hydroxide solution. The mixture was then added to ethylacetate and extracted with an aqueous solution of Rochelle's salt(sodium, potassium tartrate). The organic layers were combined anddried, and then concentrated. The residue was purified by chromatography(silica gel, hexanes in ethyl acetate) which afforded 0.93 g, (40%) ofthe title compound. MS (ESI) m/z 474 (M+H)⁺.

Intermediate 19C (S,E)-tert-butyl2-(5-(3-oxoprop-1-enyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate

The product of Intermediate 19B (0.93 g, 1.96 mmol) was dissolved indichloromethane (7.5 mL) and pyridinium dichromate (1.11 g, 2.95 mmol)was added, and the resultant mixture was stirred at room temperatureovernight. The solution had hexanes added to it, and then it wasfiltered through diatomaceous earth. The filtrate was then concentratedto a residue which was then dissolved in dichloromethane and extractedwith water. The organic layer was then dried, concentrated and theresidue purified by chromatography (silica gel, hexanes in ethylacetate) which afforded 0.3 g, (32%) of the title compound. ¹H NMR (400MHz, DMSO-d₆) δ ppm 9.65 (d, J=7.8 Hz, 1H), 8.05 (m, 1H), 7.82 (d,J=15.8 Hz, 1H), 7.70 (m, 2H), 6.87 (dd, J=15.8, 7.8 Hz, 1H), 5.70 (s,2H), 5.14 (m, 1H), 3.57 (m, 2H), 3.42 (m, 1H), 2.40 (m, 5H), 1.30 (s,4H), 0.95 (s, 5H), 0.80 (m, 2H), −0.10 (s, 9H); MS (ESI) m/z 472 (M+H)⁺.

Intermediate 20A 1-(4-chloro-2-fluoro-5-nitrophenyl)ethanone

To a solution of 4-chloro-2-fluoro-5-nitrobenzoic acid (16.0 g, 72.9mmol) in anhydrous CH₂Cl₂ (400 mL) was added oxalyl chloride (9.57 mL,109 mmol) and DMF (2 drops), and the resulting mixture was stirred atroom temperature until gas evolution ceased. The mixture wasconcentrated and dried in vacuo. In a separate, heat-dried reactionflask a mixture of ZnBr₂ (24.6 g, 109 mmol) in anhydrous THF (300 mL) at−78° C. was added a solution of CH₃MgBr (29.1 mL, 3.0 M in Et₂O, 87mmol) dropwise. The resulting mixture was stirred at −78° C. for 15minutes, and then the reaction mixture was allowed to warm to roomtemperature and stirred for 30 minutes. The mixture was cooled to −78°C. and a solution of the acid chloride in anhydrous THF (100 mL) wasadded dropwise, followed by Pd(PPh₃)₄ (1.68 g, 1.46 mmol). The resultingmixture was allowed to stir at −78° C. for 10 minutes, and was thenallowed to warm to ambient temperature and stirred for an additional 16hours. The mixture was quenched by adding aq. 1 M HCl, diluted with H₂O(100 mL), and extracted with CH₂Cl₂ (3×300 mL). The combined organicextracts were dried (MgSO₄), filtered and concentrated. The crudeproduct was purified by column chromatography (silica gel, 5% EtOAc inhexanes) to afford the title compound (11.79 g, 74%).

Intermediate 20A may also be prepared by reacting the intermediate acidchloride with dimethylmalonate, MgCl₂, and triethylamine in methylenechloride, followed by acidic hydrolysis and decarboxylation.

Intermediate 20B 2-bromo-1-(4-chloro-2-fluoro-5-nitrophenyl)ethanone

The product of Intermediate 20A (3.0 g, 13.79 mmol) dissolved in THF(100 mL) was treated with pyridinium bromide perbromide (4.63 g, 14.48mmol) portionwise over several minutes. The resulting mixture wasstirred at ambient temperature for 2 hours and then filtered. Thefiltered solids were rinsed with EtOAc, and the filtrate wasconcentrated in vacuo. The crude product was purified by columnchromatography (silica gel, 20% EtOAc in hexanes) to afford the titlecompound (3.8 g, 93%).

Intermediate 20C1,4-bis(4-chloro-2-fluoro-5-nitrophenyl)butane-1,4-dione

Intermediate 20A (4.92 g, 22.62 mmol) and Intermediate 20B (4.47 g,15.08 mmol) were processed using the method described in Intermediate 5Bto afford the title compound (4.74 g, 73%).

Intermediate 20D(1S,4S)-1,4-bis(4-chloro-2-fluoro-5-nitrophenyl)butane-1,4-diol

The product of Intermediate 20C (1.0 g, 2.309 mmol) was processed usingthe method described in Intermediate 5C to afford the title compound(0.96 g, 95%). In the chiral reduction to form Intermediate 20D, thereaction proceeds with lower stereoselectivity than in the case ofIntermediate 5C.

Intermediate 20E(1S,4S)-1,4-bis(4-chloro-2-fluoro-5-nitrophenyl)butane-1,4-diyldimethanesulfonate

To a solution of Intermediate 20D (0.95 g, 2.17 mmol) in anhydrousCH₂Cl₂ (20 mL) at 0° C. was added methanesulfonyl chloride (0.42 mL,5.43 mmol), followed by the dropwise addition of triethylamine (0.91 mL,6.52 mmol). The resulting mixture was stirred at room temperature for 90minutes, and was then concentrated in vacuo. Hexanes were added, and theresulting solids were collected by filtration, washed with H₂O, anddried in vacuo to provide the title compound (1.29 g, 100%).

Intermediate 21(1S,4S)-1-(4-chloro-2-fluoro-5-nitrophenyl)-4-(4-chloro-3-nitrophenyl)butane-1,4-diyldimethanesulfonate

Intermediate 21 can be made from Intermediate 20B and1-(4-chloro-3-nitrophenyl)ethanone (commercially available from Aldrich)following the general methods to prepare Intermediate 20E.

Intermediate 22A 1-benzyl-4-(4-methoxyphenyl)piperidin-4-ol

(4-Methoxyphenyl)magnesium bromide (0.5 M in THF, 90 mL, 45.0 mmol) wasadded slowly (˜25 minutes) via cannula to a cold (0° C.) solution of1-benzylpiperidin-4-one (5.4 mL, 30.2 mmol) in THF (60 mL). The reactionwas stirred at 0° C. under nitrogen for 2 hours. The reaction wasquenched with saturated aqueous NH₄Cl then diluted with ether. Theorganic fraction was washed with saturated aqueous NH₄Cl (2×) brine (1×)and concentrated. Purification using flash chromatography (5-100%EtOAc/hexane) provided 4.02 g (44%) of the titled compound. MS (DCI) m/z298 (M+H)⁺.

Intermediate 22B 1-benzyl-4-(4-methoxyphenyl)-1,2,3,6-tetrahydropyridine

6 M HCl (100 mL, aqueous) was added to a solution of1-benzyl-4-(4-methoxyphenyl)piperidin-4-ol (12.31 g, 41.36 mmol) indioxane (50 mL), and the reaction was heated to strong reflux (110° C.).After 2 hours, the reaction was not complete. The heat was turned offand the reaction was left to stir at ambient temperature for 2 days. Thereaction had progressed but was not complete so it was heated to 110° C.After 1 hour, the reaction was cooled and the volume was reduced byapproximately one third. The solution was then cooled in an ice bath andneutralized with NaOH pellets. The thick suspension was filtered. Theprecipitate was rinsed with water and then dried under vacuum at 70° C.to afford 6.2 g (47%) of the titled compound. ¹H NMR (400 MHz, CDCl₃) δppm 2.74-2.62 (m, 1H), 3.30-3.06 (m, 2H), 3.50 (d, J=18.5, 1H),3.67-3.56 (m, 1H), 3.82 (s, 3H), 4.03-3.90 (m, 1H), 4.21 (dd, J=5.7,13.0, 1H), 4.34 (dd, J=5.1, 13.0, 1H), 5.88 (s, 1H), 6.88 (d, J=8.7,2H), 7.32 (d, J=8.7, 2H), 7.51-7.43 (m, 3H), 7.71 (dd, J=2.7, 6.3, 2H),12.85 (s, 1H); MS (ESI) m/z 280 (M+H)⁺; MS (DCI) m/z 280 (M+H)⁺.

Intermediate 22C 4-(4-methoxyphenyl)piperidine

The product from Intermediate 22B (6.2 g) in trifluoroethanol (60 mL)was added to 20% Pd(OH)₂—C, wet (1.240 g, 8.83 mmol) in a 250 mLstainless steel pressure bottle. The mixture was shaken under 30 psi ofhydrogen at 50° C. for 23 hours. The mixture was filtered through a PTFEmembrane, concentrated and dried under vacuum to afford 4.33 g of thedesired product as the HCl salt. (HCl salt) ¹H NMR (400 MHz, CDCl₃) δppm 2.03 (d, J=13.1, 2H), 2.28-2.11 (m, 2H), 2.72 (t, J=10.2, 1H),3.08-2.91 (m, 2H), 3.62 (d, J=8.3, 2H), 3.79 (s, 3H), 6.86 (d, J=8.3,2H), 7.16 (d, J=8.5, 2H), 9.65 (d, J=83.1, 2H); MS (DCI) m/z 192 (M+H)⁺.

Intermediates 23, 24, and 25 can be Prepared Using the Methodology Usedto Prepare Intermediate 22C

Intermediate 23 4-(4-fluorophenyl)piperidine

Intermediate 24 4-(2,4-difluorophenyl)piperidine

Intermediate 25 4-(3,5-difluorophenyl)piperidine

Intermediate 26A tert-butyl-4-fluoro-4-phenylpiperidine-1-carboxylate

A solution of diethylaminosulfur trifluoride (4 mL, 32.7 mmol) indichloromethane (10 mL) was added to a cold (−78° C.; dry ice/acetonebath) solution of tert-butyl 4-hydroxy-4-phenylpiperidine-1-carboxylate(8.05 g, 29.0 mmol) in dichloromethane (100 mL) under nitrogen. Thereaction was stirred at −78° C. for ˜1 hour. The reaction was removedfrom the bath and warmed to ambient temperature then stirred another 30minutes. The reaction was quenched with saturated aqueous NaHCO₃ (100mL). The organic fraction was washed with brine (˜50 mL). Then3-chloroperoxybenzoic acid (1.0995 g, 6.37 mmol) was added to thereaction and stirred at ambient temperature for 30 minutes. This stepwas quenched with saturated aqueous NaHCO₃ (100 mL). The organicfraction was washed with saturated aqueous NaHCO₃ (1×100 mL), water(1×100 mL), and brine (1×100 mL), dried (MgSO₄), tested for peroxide(3-10 ppm) and concentrated to light yellow oil. The oil was dried undervacuum to afford 8.27 g (100%) of the titled compound. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.42 (d, J=5.7, 9H), 1.96-1.85 (m, 3.5H), 2.03 (ddd,J=5.2, 13.3, 17.8, 1.5H), 3.06 (s, 2H), 3.98 (d, J=12.0, 2H), 7.33 (d,J=7.1, 1H), 7.46-7.36 (m, 4H); MS (DCI) m/z 280 (M+H⁺, 60%), 297 (M+NH₄⁺, 100%).

Intermediate 26B 4-fluoro-4-phenylpiperidine

Hydrochloric acid (4 M in dioxane, 20 mL, 80 mmol) was added to asolution of tert-butyl 4-fluoro-4-phenylpiperidine-1-carboxylate (8.27g, 29.6 mmol) in dioxane (10 mL). The reaction was stirred at ambienttemperature for 4 hours. The reaction was concentrated to an oil. Etherwas added, and the resulting solid was sonicated and then stirredvigorously overnight to provide a tan solid. The solid was filtered,rinsed with ether and dried under vacuum at 60° C. for 3 hours toprovide 5.56 g (87%) of the titled product. MS (DCI) m/z 180 (M+H)⁺.

Intermediate 27A tert-butyl 4-(hydroxydiphenylmethyl)piperidine-1-carboxylate

A solution of di-tert-butyl dicarbonate (8.43 mL, 36.7 mmol) indichloromethane (15 mL) was added to a solution ofdiphenyl(piperidin-4-yl)methanol (8.0721 g, 30.2 mmol) indichloromethane (100 mL); triethylamine (5.1 mL, 36.6 mmol) was addedand the reaction was stirred at ambient temperature for 2 hours. Thereaction was diluted with dichloromethane and then washed with saturatedaqueous NaHCO3 (2×), water (1×), and brine (1×), dried (MgSO₄) andconcentrated to afford 11.63 g (105%) of the titled compound. MS (ESI)m/z 367 (M+H)⁺, 366 (M−H)⁺.

Intermediate 27B 4-(fluorodiphenylmethyl)piperidine

The title compound was prepared from tert-butyl4-(hydroxydiphenylmethyl)piperidine-1-carboxylate using the generalmethods of Intermediates 26A and 26B. 3.37 g (100%) as HCl salt, MS(DCI) m/z 270 (M+H)⁺.

General Procedures General Procedure 1 Synthesis of 4-amino substitutedanilines

Intermediate anilines having an amino group para to the aniline can bemade using a two-step procedure. Fluoronitrobenzenes,fluoronitropyridines, or fluoronitropyrimidines can be reacted in Step 1with an appropriate amine

where

represents any amine group that can be present in R_(M) and attachedthrough nitrogen, in the presence of dibasic potassium phosphate(equivalents) or potassium carbonate in a solvent such as DMSOoptionally with heating and optional microwave irradiation. Step 2 canbe accomplished by standard nitro reduction conditions such as catalytichydrogenation using palladium on carbon or Raney-nickel. Alternatively,the reduction can be effected with iron/ammonium chloride inTHF/methanol/water as solvent. Where the group

is an optionally substituted cyclic amine (e.g., piperidine,pyrrolidine), the optionally substituted cyclic amines can be accessedas described herein or using generally known methodologies. See forexample the methods shown in Patel et al. J Medicinal Chemistry 49(25)7450 (2006).

Illustration of General Procedure 1: General Procedure 1A Step 11-(2,6-difluoro-4-nitrophenyl)-4-phenylpiperidine

In a 100 mL round-bottom flask was mixed 3,4,5-trifluoronitrobenzene(1.751 mL, 15 mmol) and potassium phosphate, dibasic (5.23 g, 30.0 mmol)in DMSO (15.00 mL) to give a yellow suspension. 4-Phenylpiperidine(2.419 g, 15.00 mmol) was added portion-wise as a solid over 10 minutesto produce a deeper yellow suspension and a mild exotherm. The mixturewas stirred for 1 hour and partitioned between EtOAc and water. TheEtOAc layer was washed 2× by 50 mL each with water and brine, dried(Na₂SO₄), filtered and concentrated to give the title compound as ayellow solid (4.53 g, 95% yield).

Step 2 3,5-difluoro-4-(4-phenylpiperidin-1-yl)aniline

In a 500 mL round-bottom flask was added1-(2,6-difluoro-4-nitrophenyl)-4-phenylpiperidine (4.53 g, 14.23 mmol),iron (3.97 g, 71.2 mmol), and ammonium chloride (1.142 g, 21.35 mmol) ina solvent mixture of EtOH (60 mL)/THF (60 mL)/water (20 mL). The mixturewas refluxed for 3 hours with vigorous stirring, cooled, filteredthrough diatomaceous earth and the filtrate was concentrated. Theresidue was partitioned between ethyl acetate and water. The organiclayer was washed with brine, dried (Na₂SO₄), filtered and evaporated togive the title compound as yellow solid (3.93 g, 96% yield). ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.63-1.81 (m, 4H) 2.54-2.64 (m, 1H) 2.95-3.03 (m,2H) 3.09 (t, J=10.57 Hz, 2H) 5.42 (s, 2H) 6.10-6.21 (m, 2H) 7.15-7.22(m, 1H) 7.25-7.34 (m, 4H); MS (ESI+) m/z 289 (M+H)⁺.

Illustration of General Procedure 1: General Procedure I B Step 15-nitro-2-(pyrrolidin-1-yl)pyridine

To a slurry of 2-chloro-5-nitropyridine (10 g, 63.1 mmol) in EtOH (100mL) at room temperature was added pyrrolidine (15.72 mL, 189 mmol) andthe mixture was heated at 70° C. for 18 hours. The cooled solution wasconcentrated in vacuo and the residue partitioned between CH₂Cl₂ and 1 MNaOH. The organic layer was dried (Na₂SO₄), filtered and solvent removedin vacuo to give title compound (9.52 g, 78%). MS (ESI) m/z 194 (M+H)⁺.

Step 2 6-(pyrrolidin-1-yl)pyridin-3-amine

5-Nitro-2-(pyrrolidin-1-yl)pyridine (9.52 g, 49.3 mmol) was dissolved inTHF (50 mL) and DMF (40 mL) and added to a pressure bottle containingRaney-nickel 2800, water slurry (45%) (9.52 g, 162 mmol). The mixturewas stirred for 2 hours at 30 psi under H₂ gas. The solution wasfiltered through a nylon membrane, washed with CH₃OH and the filtrateconcentrated in vacuo to give the title compound (7.78 g, 97%). ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.81-1.91 (m, 4H) 3.17-3.29 (m, 4H) 4.30 (s,2H) 6.25 (d, J=8.7, 1H), 6.90 (dd, J=2.8, 8.7, 1H), 7.55 (d, J=2.6, 1H);MS (ESI) m/z 164 (M+H)⁺.

Illustration of General Procedure 1, step 2: General Procedure 1C

4-(3,5-dimethylpiperidin-1-yl)-3,5-difluoroaniline

1-(2,6-Difluoro-4-nitrophenyl)-3,5-dimethylpiperidine (14.01 g, 51.8mmol) and THF (240 mL) were added to Raney-nickel 2800, water slurry(14.01 g, 239 mmol) in a 500 mL stainless steel pressure bottle. Themixture was stirred for 8 hours at 30 psi and room temperature. Themixture was filtered through a nylon membrane and concentrated to givethe title compound.

Illustration of General Procedure 1, step 2: General Procedure 1D

3-methyl-4-(piperidin-1-yl)aniline

To a solution of 1-(2-methyl-4-nitrophenyl)piperidine (6.75 g, 30.6mmol) in ethyl acetate (50 mL) was added 10% palladium on carbon (0.033g, 0.306 mmol) and the mixture hydrogenated (hydrogen balloon) at roomtemperature for 20 hours. The mixture was then filtered throughdiatomaceous earth and washed with ethyl acetate; the filtrate was thenconcentrated to afford 5.5 g (94%) of the title compound. MS (ESI) m/z191 (M+H)⁺.

Illustration of General Procedure 1, step 1: General Procedure 1E

1-(4-nitrophenyl)-4-phenylpiperidine

An oven-dried 20 mL microwave tube was charged with 4-fluoronitrobenzene(0.752 mL, 7.02 mmol), 4-phenylpiperidine (1.166 g, 7.02 mmol), andpotassium carbonate (0.970 g, 7.02 mmol) under nitrogen, anhydrous DMSO(7 mL) was added, the tube was sealed with an aluminum crimp cap, andheated in a microwave reactor (Personal Chemistry, 300 W, 2.4 bar) at190° C. for 10 minutes. TLC (SiO₂, 5% EtOAc/hexanes) showed completereaction. The reaction was poured into water (50 mL), stirred for 5minutes, and vacuum filtered in a Büchner funnel. The collected yellowsolids were washed with water (2×10 mL) and Et₂O (5 mL), and the brightyellow solid was dried in vacuo to provide the title compound (1.712 g,6.06 mmol, 86%). ¹H NMR (400 MHz, CDCl₃) δ ppm 1.73-1.90 (m, 2H), 2.00(d, J=13.34 Hz, 2H), 2.73-2.86 (m, 1H), 3.02-3.17 (m, 2H), 4.10 (d,J=13.23 Hz, 2H), 6.87 (d, J=9.43 Hz, 2H), 7.23 (t, J=7.75 Hz, 3H), 7.33(t, J=7.43 Hz, 2H), 8.14 (d, J=9.33 Hz, 2H); MS (ESI+) m/z 283 (M+H)⁺.

The following amines can be made using methods shown in the foregoingGeneral Procedure 1:

-   4-(4,4-dimethylpiperidin-1-yl)-3,5-difluoroaniline;-   4-(2-azabicyclo[2.2.2]octan-2-yl)-3,5-difluoroaniline;-   3,5-difluoro-4-(4-isopropylpiperidin-1-yl)aniline;-   3,5-difluoro-4-(4-(trifluoromethyl)piperidin-1-yl)aniline;-   4-(4-tert-butylpiperidin-1-yl)-3,5-difluoroaniline;-   3,5-difluoro-4-(6-azaspiro[2.5]octan-6-yl)aniline;-   4-(3,3-dimethylazetidin-1-yl)-3,5-difluoroaniline;-   4-(4,4-difluoropiperidin-1-yl)-3,5-difluoroaniline;-   3,5-difluoro-4-(4-fluoropiperidin-1-yl)aniline;-   3,5-difluoro-4-(piperidin-1-yl)aniline;-   2,3,5,6-tetrafluoro-4-(piperidin-1-yl)aniline;-   3-methyl-4-(piperidin-1-yl)aniline;-   3,5-difluoro-4-((3aR,7aS)-1H-isoindol-2(3H,3aH,4H,5H,6H,7H,7aH)-yl)aniline;-   N¹-tert-butyl-2-fluorobenzene-1,4-diamine;-   3,5-difluoro-4-(4-methylpiperidin-1-yl)aniline;-   3,5-dichloro-4-(piperidin-1-yl)aniline;-   2,5-difluoro-4-(piperidin-1-yl)aniline;-   4-((2R,6S)-2,6-dimethylpiperidin-1-yl)-3,5-difluoroaniline;-   2,3,5-trifluoro-4-(piperidin-1-yl)aniline;-   4-((1R,5S)-3-azabicyclo[3.2.0]heptan-3-yl)-3,5-difluoroaniline;-   3-fluoro-4-(piperidin-1-yl)aniline;-   3,5-difluoro-4-(3-azaspiro[5.5]undecan-3-yl)aniline;-   3,5-difluoro-4-(isoindolin-2-yl)aniline;-   3,5-difluoro-4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)aniline;-   4-(4-phenyl-5,6-dihydropyridin-1(2H)-yl)aniline;-   3-fluoro-4-(4-phenylpiperidin-1-yl)aniline;-   4-(4,4-diphenylpiperidin-1-yl)-3,5-difluoroaniline;-   4-(4-phenylpiperidin-1-yl)aniline;-   1-(1-(4-amino-2,6-difluorophenyl)-4-phenylpiperidin-4-yl)ethanone;-   3,5-difluoro-4-(4-(3-phenylpropyl)piperidin-1-yl)aniline;-   3,5-difluoro-4-(8-azaspiro[4.5]decan-8-yl)aniline;-   3,5-difluoro-4-(3-phenylpiperidin-1-yl)aniline;-   3,5-difluoro-4-(3-phenylpyrrolidin-1-yl)aniline;-   3,5-difluoro-4-(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)aniline;-   3,5-difluoro-4-(4-phenylpiperazin-1-yl)aniline;-   4-(4-(2,6-difluorophenyl)piperazin-1-yl)-3,5-difluoroaniline;-   3,5-difluoro-4-(4-(pyrimidin-2-yl)piperazin-1-yl)aniline;-   3,5-difluoro-4-(2-phenylmorpholino)aniline;-   (S)-3,5-difluoro-4-(2-phenylmorpholino)aniline-   3,5-difluoro-4-(2-phenylpiperidin-1-yl)aniline;-   4-((2S,6R)-2,6-dimethylmorpholino)-3,5-difluoroaniline;-   4-(4-cyclohexylpiperidin-1-yl)-3,5-difluoroaniline;-   4-(4-benzylpiperidin-1-yl)-3,5-difluoroaniline;-   3,5-difluoro-4-(4-(4-methoxyphenyl)piperidin-1-yl)aniline;-   3,5-difluoro-4-(4-(4-fluorophenyl)piperidin-1-yl)aniline;-   4-(4-(3,4-difluorophenyl)piperidin-1-yl)-3,5-difluoroaniline;-   4-(4-(3,5-difluorophenyl)piperidin-1-yl)-3,5-difluoroaniline;-   3,5-difluoro-4-(4-fluoro-4-phenylpiperidin-1-yl)aniline;-   3,5-difluoro-4-(4-(fluorodiphenylmethyl)piperidin-1-yl)aniline;-   4-(4-fluoro-4-phenylpiperidin-1-yl)aniline;-   3,5-difluoro-4-(4-(pyridin-2-yl)piperidin-1-yl)aniline;-   3,5-difluoro-4-(4-(naphthalen-2-yl)piperidin-1-yl)aniline;-   3,5-difluoro-4-(4-(naphthalen-1-yl)piperidin-1-yl)aniline; and-   3,5-difluoro-4-(4-(4-(trimethylsilyl)phenyl)piperidin-1-yl)aniline.

General Procedure 1.1. 4-Alkoxy-Substituted Aniline

Intermediate anilines having an alkoxy substituent para to the anilinemay be prepared through a two-step procedure wherein G₁₀ is —OR_(S)(e.g., —O-t-butyl, —O-isopropyl, —O—CH₂—(3-ethyloxetan-3-yl),—O—CH₂—(1,3-dioxolan-4-yl), —O-cyclopentyl, —O-cyclohexyl,—O—(1,3-dioxan-5-yl)). In Step 1, fluoronitrobenzenes can be reactedwith an appropriate alcohol and base (e.g., Cs₂CO₃, potassiumtert-butoxide) in DMSO or like solvent with heating to between 50-100°C. Step 2 can be accomplished by standard nitro reduction conditionssuch as catalytic hydrogenation using palladium on carbon or Raneynickel as described elsewhere herein. Alternatively, the reduction canbe effected with iron/ammonium chloride in THF/methanol/water assolvent.

Illustration of General Procedure 1.1: General Procedure 1.1A Step 13-ethyl-3-((4-nitrophenoxy)methyl)oxetane

To a solution of 4-fluoronitrobenzene (3.76 mL, 35.4 mmol) in DMSO (35mL) at room temperature was added cesium carbonate (7.09 mL, 89.0 mmol)followed by 3-ethyl-3-oxetanemethanol (4.48 mL, 42.5 mmol). The mixturewas heated to 70° C. for 2 hours. After cooling water was added and theresulting precipitate was filtered, washed with water, and dried in avacuum oven to provide the title compound (8.28 g, 98% yield).

Step 2 4-((3-ethyloxetan-3-yl)methoxy)aniline

To a solution of 3-ethyl-3-((4-nitrophenoxy)methyl)oxetane (8.28 g, 34.9mmol) in a 3:3:1 mixture of THF:EtOH:water (140 mL) at room temperaturewas added ammonium chloride (2.80 g, 52.3 mmol) followed by iron powder(9.74 g, 174 mmol). The mixture was heated to 90° C. for 1 hour, then itwas filtered hot through diatomaceous earth with a THF wash to completethe transfer. The filtrate was concentrated under reduced pressure, andthe residue was taken up in ethyl acetate then washed with brine, dried(Na₂SO₄), and concentrated to provide the title compound (7.12 g, 98%yield) without further purification.

The following amines can be made using methods shown in the foregoingGeneral Procedure 1:

-   4-((3-ethyloxetan-3-yl)methoxy)-3,5-difluoroaniline;-   4-((1,3-dioxolan-4-yl)methoxy)aniline;-   4-(1,3-dioxan-5-yloxy)aniline.

General Procedure 1.2. Aniline Formation Through Suzuki-Type Reaction

Certain intermediate anilines can be made from a bromide, iodide, ortriflate (i.e., X_(1.2)=Br, I, or OTf) through a Suzuki, Stille, orother similar transition metal-mediated carbon-carbon bond formingreaction to form products where R_(M1) _(—) ₂ is cycloalkyl, aryl,heteroaryl, or cycloalkenyl. Above is an illustration of the processconducted on an aniline, however the process can be done also usingother functionality which can be converted to an aniline (e.g., a nitrogroup).

Illustration of General Procedure 1.2. General Procedure 1.2A.4-(cyclohexen-1-yl)-3-fluoroaniline

In a pressure tube, a solution of 3-fluoro-4-iodoaniline (2.29 g, 9.66mmol) and potassium carbonate (1.74 g, 12.58 mmol) in 4:1dimethoxyethane-water (33 mL) was degassed by nitrogen sparge for 40minutes, followed by addition of 1-cyclohexenyl boronic acid pinacolester (2.7 mL, 2.61 g, 12.56 mmol). Then1,1′-bis(diphenylphosphino)ferrocene palladium (II) chloridedichloromethane complex (237 mg, 0.29 mmol) was added followed bydegassing for another 5 minutes. The pressure tube was sealed and warmedat 100° C. for 18 hours. The mixture was cooled and diluted with ethylacetate, followed by extraction with water and saturated sodium chloridesolution. The solution was dried (Na₂SO₄) and stirred with3-(mercaptopropyl) silica gel for 1 hour. Concentration in vacuoafforded a brown oil, which was chromatographed over a 340 g silica gelcartridge, eluting with 10-100% ethyl acetate in hexanes. Theseprocedures afforded the title compound (1.16 g, 63%) as a light brownoil. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.00 (m, 1H), 6.37 (m, 2H), 5.84 (s,1H), 3.71 (br s, 2H), 2.32 (m, 2H), 2.17 (m, 2H), 1.73 (m, 2H), 1.65 (m,2H); MS (+DCI) m/z (rel abundance) 192 (100, M+H).

Illustration of General Procedure 1.2. General Procedure 1.2B.4-cyclopropyl-3,5-difluoroaniline

To a pressure tube was added 4-bromo-3,5-difluoroaniline (1.0 g, 4.8mmol), cesium carbonate (4.7 g, 14.4 mmol), toluene (10 mL) and water (1mL). The solution was de-gassed with N₂ gas for 30 minutes, followed bythe addition of cyclopropyltrifluoro-borate, potassium salt (0.8 g, 5.3mmol), di(1-adamantyl)-n-butylphosphine hydroiodide (0.07 g, 0.14 mmol)and palladium(II) acetate (0.02 g, 0.096 mmol). De-gassing was continuedfor 5 minutes, the tube was sealed and heated at 100° C. for 18 hours.The cooled solution was diluted with EtOAc, washed with H₂O and brine,dried (Na₂SO₄), and filtered. The filtrate was treated with3-mercaptopropyl silica gel for 1 hour. The mixture was filtered andconcentrated to give crude product which was purified by flashchromatography (0-30% EtOAc/hexane) to give the title compound (0.67 g,4.0 mmol, 82%).

Illustration of General Procedure 1.2. General Procedure 1.2C.4-cyclopropyl-2-fluoro-1-nitrobenzene

A solution of 4-bromo-2-fluoronitrobenzene (0.5 g, 2.27 mmol),cyclopropylboronic acid (0.293 g, 3.41 mmol), tribasic potassiumphosphate (0.965 g, 4.55 mmol), tricyclohexylphosphoniumtetrafluoroborate (0.021 g, 0.057 mmol) and palladium (II) acetate (6.12mg 0.027 mmol) in 11 mL of a toluene-water mixture 10:1 (v/v) wasnitrogen purged-vacuum degassed three times. The reaction mixture wasthen heated in an oil bath at 85° C. for four hours. The reactionmixture was partitioned with ethyl acetate and the organic phase waterwashed then dried (Na₂SO₄) and concentrated. The reaction mixture waspartitioned between ethyl acetate and water. The organic phase waswashed with water, dried (Na₂SO₄) and concentrated. The crude productwas purified by chromatography on silica gel (ethyl acetate-hexane) toprovide the title compound (0.382 g, 88%) as a yellow oil.

General Procedure 1.3

Certain intermediate anilines can be made using the general sequenceoutlined above and illustrated below. The sequence consists of reactionof a fluoronitrobenzene with a cyclic amine moiety (Step 1); conversionto a vinylic coupling partner (Steps 2 and 3); coupling of the vinyliccoupling partner with another suitable partner (Step 4); and reductionof the nitro group and olefin (Step 5). Alternatively, this route may beadapted to prepare anilines wherein the olefin remains intact throughselective reduction of the nitro group. Carbon-carbon bond formingreactions that may be suitable for Step 4 include, for example, theSuzuki reaction, the Stille reaction, or the Negishi reaction.

Illustration of General Procedure 1.3: General Procedure 1.3A Step 18-(2,6-difluoro-4-nitrophenyl)-1,4-dioxa-8-azaspiro[4.5]decane

A mixture of 1,2,3-trifluoro-5-nitrobenzene (4.0 mL, 34.3 mmol),1,4-dioxa-8-azaspiro[4.5]decane (6.59 mL, 51.4 mmol) and potassiumcarbonate (5.68 g, 41.1 mmol) in DMSO (35 mL) was heated at 100° C. for3 hours and then cooled to room temperature. The mixture was partitionedbetween water and EtOAc, and the organic layer was dried over Na₂SO₄,filtered and concentrated in vacuo. The crude product was purified bycolumn chromatography on silica gel using a solvent gradient of 0-20%EtOAc in hexanes to give a yellow oil.

Step 2

1-(2,6-difluoro-4-nitrophenyl)piperidin-4-one

The crude 8-(2,6-difluoro-4-nitrophenyl)-1,4-dioxa-8-azaspiro[4.5]decanefrom the preceding procedure was dissolved in 4:1 acetone:water (100mL). Concentrated HCl (5 mL) was added, and the resulting mixture wasstirred at 50° C. for 8 hours and then cooled to room temperature. Themixture was concentrated in vacuo to approximately 20 mL, which wascarefully added to concentrated aq. NaHCO₃ (100 mL) and extracted withEtOAc (2×100 mL). The combined organic extracts were dried over Na₂SO₄,filtered and concentrated in vacuo. The crude product was trituratedwith Et₂O and hexanes to give a bright-yellow solid that was collectedand dried to provide the title compound (7.13 g, 81%).

Step 3 1-(2,6-difluoro-4-nitrophenyl)-1,2,3,6-tetrahydropyridin-4-yltrifluoromethanesulfonate

To a solution of 1-(2,6-difluoro-4-nitrophenyl)piperidin-4-one (5.0 g,19.52 mmol) in anhydrous THF (50 mL) at −78° C. under a dry N₂atmosphere was added a 1 M THF solution of lithiumbis(triethylsilyl)amide (29.3 ml, 29.3 mmol) in THF dropwise over 10minutes. The resulting deep red solution was stirred at −78° C. for 5minutes and1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide(7.67 g, 21.47 mmol) was added. The resulting mixture was stirred at−78° C. for 1 hour, and then the mixture was allowed to warm to roomtemperature. The mixture was diluted with EtOAc (100 mL) and washed with1 N aq. NaOH (50 mL) and water (50 mL), and dried over Na₂SO₄. Thedrying agent was filtered off, and the solvent was removed in vacuo togive a crude product that was purified by column chromatography onsilica gel using a solvent gradient of 0-40% EtOAc in hexanes. The titlecompound was obtained as a yellow oil that crystallized in vacuo (6.12g, 81%).

Step 4 (Suzuki Reaction)

1-(2,6-difluoro-4-nitrophenyl)-4-(3,4-difluorophenyl)-1,2,3,6-tetrahydropyridine

A mixture of1-(2,6-difluoro-4-nitrophenyl)-1,2,3,6-tetrahydropyridin-4-yltrifluoromethanesulfonate (1.18 g, 3.04 mmol),2-(3,4-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.02 g,4.25 mmol), lithium chloride (0.387 g, 9.12 mmol) and a 2.0 M aq.solution of sodium carbonate (4.56 mL, 9.12 mmol) in anhydrous DME (15mL) was vigorously stirred while bubbling with N₂ gas for 20 minutes.Tetrakis(triphenylphosphine)palladium(0) (0.176 g, 0.152 mmol) wasadded, and the resulting mixture was degassed for 5 minutes more. Thereaction flask was equipped with a condenser and placed in 100° C. oilbath. The dark mixture was stirred at 100° C. under a dry N₂ atmospherefor 16 hours, and was then cooled to room temperature and partitionedbetween water (50 mL) and EtOAc (2×50 mL). The combined organic layerswere dried over Na₂SO₄, filtered and concentrated in vacuo, and thecrude product was purified by column chromatography on silica gel usinga solvent gradient of 0-40% EtOAc in hexanes to provide a yellow oilthat solidified on standing. The solid was triturated with Et₂O andhexanes, filtered and dried to provide the title compound (0.67 g, 63%).

Step 5

(4-(4-(3,4-difluorophenyl)piperidin-1-yl)-3,5-difluoroaniline

To a solution of1-(2,6-difluoro-4-nitrophenyl)-4-(3,4-difluorophenyl)-1,2,3,6-tetrahydropyridine(0.67 g, 1.90 mmol) in THF (20 mL) was added 10% Pd on carbon (50 mg).The reaction flask was flushed with N₂ gas, and the resulting mixturewas vigorously stirred under 1 atm H₂ gas for 24 hours. The mixture wasfiltered through diatomaceous earth and concentrated in vacuo to givethe title compound as a solid (0.62 g, 100%).

The following amines can be made using methods shown in the foregoingGeneral Procedure 1.3:

-   3,5-difluoro-4-(4-(4-fluorophenyl)piperidin-1-yl)aniline;-   3,5-difluoro-4-(4-(3-(trimethylsilyl)phenyl)piperidin-1-yl)aniline;    and-   3,5-difluoro-4-(4-(5-methylthiophen-2-yl)piperidin-1-yl)aniline.    General Procedure 2. Pyrrolidine Formation from Amine and Dimesylate    (5)

A dimesylate (5) (1 equivalent), as a single stereoisomer or mixture ofisomers, may be reacted with between 1 to 20 equivalents of an amine,D-NH₂, either neat, or in solvents such as tetrahydrofuran or2-methyltetrahydrofuran with or without a co-solvent such as DMF, atabout room temperature to about 100° C., to give the pyrrolidines suchas Formula (6). Where fewer equivalents of amine, D-NH₂, are employed(i.e., 1-2 equivalents), a base such as diisopropylethylamine can beadded to promote the reaction. For example, the reaction of a dimesylate(1 equivalent) with excess of an aniline, D-NH₂, (about 5-10equivalents) can be conducted by heating from 50 to 65° C. in2-methyltetrahydrofuran or DMF until completion of the reaction. Or thedimesylate (1 equivalent) can be reacted neat with excess of an aniline,D-NH₂, (about 15-20 equivalents) at room temperature or with heating toaround 65° C. The reaction can be partitioned between an organic solvent(e.g., ethyl acetate) and dilute aqueous HCl, followed by separation ofthe organic layer, optional washing of the organic with water, dryingthe organic layer with a drying agent (e.g., MgSO₄, Na₂SO₄), filtrationand evaporation of solvent. The product can be purified by columnchromatography over silica gel, eluting with standard solvents such asmixtures of ethyl acetate and hexane; or alternatively the product canbe purified by trituration or recrystallization.

Illustration of General Procedure 2: General Procedure 2A(2S,5S)-1-(4-tert-butylphenyl)-2,5-bis(4-nitrophenyl)pyrrolidine

To the crude product solution of Intermediate 6C (7.35 g, 13.39 mmol)was added 4-tert-butylaniline (13.4 g, 90 mmol) at 23° C. over 1 minute.The reaction was heated to 65° C. for 2 hours. After completion, thereaction mixture was cooled to 23° C. and diluted with2-methyltetrahydrofuran (100 mL) and 1 M HCl (150 mL). Afterpartitioning the phases, the organic phase was treated with 1 M HCl (140mL), 2-methyltetrahydrofuran (50 mL), and 25 wt % aq. NaCl (100 mL), andthe phases were partitioned. The organic phase was washed with 25 wt %aq. NaCl (50 mL), dried over MgSO₄, filtered, and concentrated in vacuoto approximately 20 mL. Heptane (30 mL) and additional2-methyltetrahydrofuran were added in order to induce crystallization.The slurry was concentrated further, and additional heptane (40 mL) wasslowly added and the slurry was filtered, washing with2-methyltetrahydrofuran:heptane (1:4, 20 mL). The solids were suspendedin CH₃OH (46 mL) for 3 hours, filtered, and the wet solid was washedwith additional CH₃OH (18 mL). The solid was dried at 45° C. in a vacuumoven for 16 hours to provide the title compound (3.08 g).

General Procedure 3. Pyrrolidine Formation from Amine andBisbromophenyldimesylate

General Procedure 3 can be conducted using conditions substantiallysimilar to the conditions of General Procedure 2.

Illustration of General Procedure 3: General Procedure 3A(2S,5S)-2,5-bis(4-bromophenyl)-1-(4-tert-butylphenyl)pyrrolidine

Intermediate 7C was dissolved in anhydrous DMF (5 mL), and4-tert-butylaniline (2.39 mL, 15 mmol) was added. The resulting mixturewas stirred at 40° C. for 4 hours, and then it was partitioned between 1N aq. HCl (30 mL) and EtOAc (30 mL). The organic layer was washed withH₂O and dried over Na₂SO₄. The drying agent was filtered off, thesolvent was removed in vacuo, and the crude product was purified bycolumn chromatography on silica gel using a solvent gradient of 0-20%EtOAc in hexanes. The title compound was obtained as a colorless solid(0.71 g, 92%). ¹H NMR indicated this material was a 87:13 mixture oftrans:cis pyrrolidine isomers.

General Procedure 4. Pyrrolidine Formation from Amine and Dimesylate(52)

General Procedure 4 can be conducted using conditions substantiallysimilar to the conditions of General Procedure 2. For example, adimesylate (52) (1 equivalent), as a single stereoisomer or mixture ofisomers, may be reacted with between 1 to 20 equivalents of an amineD-NH₂ either neat, or in solvents or mixtures of solvents includingethanol, acetonitrile, methylene chloride, tetrahydrofuran,2-methyltetrahydrofuran, DMF, or DMA, at about room temperature to about100° C., to give the pyrrolidines such as Formula (53). Alternatively, adimesylate (52) (1 equivalent) can be reacted with an amine D—NH₂ (1-4equivalents) in the presence of a base like diisopropylethylamine (3-10equivalents) in solvents or mixtures of solvents including methylenechloride, tetrahydrofuran, 2-methyltetrahydrofuran, DMF, or DMA attemperatures from around room temperature to about 70° C. Where fewerequivalents of amine D-NH₂ are employed (i.e., 1-2 equivalents), greateramounts of a base (about 8-10 equivalents) such as diisopropylethylaminemay be added to promote the reaction. For less reactive amines (e.g.,2,5-difluoro-4-(trifluoromethyl)aniline, 2-fluoropyridin-4-amine), areaction time of several days may be required. The reaction can bepartitioned between an organic solvent (e.g., ethyl acetate) and wateror dilute aqueous HCl, followed by separation of the organic layer,optional washing of the organic with water and/or brine, drying theorganic layer with a drying agent (e.g., MgSO₄, Na₂SO₄), filtration andevaporation of solvent. The product (53) can be purified by columnchromatography over silica gel, eluting with standard solvents such asmixtures of ethyl acetate and hexane or methylene chloride in hexane.The methylene chloride/hexane system can be used to remove residualamine in cases where the reaction is quenched in water instead ofaqueous HCl. In such cases a second chromatography using an ethylacetate/hexane system may be necessary to separate cis from transpyrrolidine products. Or alternatively, the product can be purified bytrituration or recrystallization.

Illustration of General Procedure 4: General Procedure 4A(2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)-1-(4-cyclohexylphenyl)pyrrolidine

To Intermediate 5D (4.99 mmol) in dimethylformamide (8 mL) was added4-cyclohexylaniline (5.24 g, 29.9 mmol), and the solution was heated at65° C. for 2 hours. The reaction mixture was then poured into 1 M HCland extracted into dichloromethane. The organic phase was concentratedand purified with a CombiFlash® 80 g silica column eluting with 0-20%ethyl acetate in hexanes to give 1.38 g (51%) of the title compound.

Illustration of General Procedure 4: General Procedure 4B1-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-4-phenylpiperidine

A 250 mL flask was charged with3,5-difluoro-4-(4-phenylpiperidin-1-yl)aniline (3.1 g, 10.76 mmol),Intermediate 5D (5.0 g, 8.97 mmol), DMF (15 mL) anddiisopropylethylamine (15.7 mL, 90 mmol). The resulting slurry wasplaced in a 60° C. oil bath and heated under N₂ for 18 hours. The ambersolution was cooled, diluted with 300 mL of ethyl acetate, washed 2×100mL water, 2×100 mL with 1 N HCl, brine, dried (Na₂SO₄), filtered andconcentrated. The crude material was flash chromatographed on a 330 gsilica cartridge eluting with 50-80% dichloromethane in hexane to removeunreacted aniline. The column fractions containing the product werecombined and concentrated to give an orange solid that was dissolved in20 mL of hot ethyl acetate, treated with 15 mL hexane, and allowed tostir at ambient temperature overnight producing a precipitate (cispyrrolidine) that was removed by filtration. The filtrate wasconcentrated and chromatographed again on a 330 g silica cartridgeeluting with 40-70% methylene chloride in hexane to give1-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-4-phenylpiperidineas an orange foam (2.26 g, 36%). MS (ESI+) m/z 653 (M+H)⁺.

Illustration of General Procedure 4: General Procedure 4C1-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2-fluorophenyl)-4-phenylpiperidine

Intermediate 5D (6.0 g, 10.76 mmol),3-fluoro-4-(4-phenylpiperidin-1-yl)aniline (4.37 g, 16.15 mmol), anddiisopropylethylamine (15.04 mL, 86 mmol) were combined inN,N-dimethylacetamide (15 mL) and heated at 60° C. for 3 hours. Thesolution was diluted with water, extracted into dichloromethane andwashed with brine. The organics were concentrated and purified bychromatography, eluting with 30-100% dichloromethane in hexanes to give5.05 g (74%) of a yellow solid.

Illustration of General Procedure 4: General Procedure 4D(2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)-1-(4-ethoxyphenyl)pyrrolidine

Intermediate 5D (2.5805 g, 4.63 mmol) and 4-ethoxyaniline (2.4 mL, 18.60mmol) were combined in DMF (30 mL) and stirred at room temperatureovernight. The reaction was diluted with EtOAc/ether and washed withwater (2×), brine (1×) and concentrated. The residue was purified bysilica gel chromatography (hexane/EtOAc) to provide 1.8 g of the titlecompound (77%).

Illustration of General Procedure 4: General Procedure 4E1-(4-((2R,5R)-2,5-bis(4-chloro-2-fluoro-5-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)piperidine

To a solution of(1S,4S)-1,4-bis(4-chloro-2-fluoro-5-nitrophenyl)butane-1,4-diyldimethanesulfonate (500 mg, 0.843 mmol) in CH₃CN (4.5 ml) was added3,5-difluoro-4-(piperidin-1-yl)aniline (358 mg, 1.685 mmol) and Hunig'sbase (0.736 mL, 4.21 mmol). The suspension was heated at 75° C. for 24hours. Solvent was removed by rotary evaporation and the residue wasdissolved in EtOAc, washed with 1 N HCl, H₂O, brine, dried (MgSO₄),filtered and concentrated. The crude product was chromatographed on anISCO 24 g silica gel cartridge eluting with 20-70% CH₂Cl₂/hexane toprovide the title compound with some of the correspondingcis-pyrrolidine isomer.

The following substituted pyrrolidines can be made using the foregoinggeneral methods:

-   1-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-4,4-dimethylpiperidine;-   2-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-2-azabicyclo[2.2.2]octane;-   1-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-4-isopropylpiperidine;-   1-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-4-(trifluoromethyl)piperidine;-   1-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-4-tert-butylpiperidine;-   6-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-6-azaspiro[2.5]octane;-   1-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-4,4-dimethylpiperidine;-   (2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)-1-(4-(3,3-dimethylazetidin-1-yl)-3,5-difluorophenyl)pyrrolidine;-   (2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)-1-(4-phenoxyphenyl)pyrrolidine;-   1-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)phenyl)pyridin-2(1H)-one;-   (2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)-1-(2,5-difluoro-4-(trifluoromethyl)phenyl)pyrrolidine;-   2-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)phenyl)oxazole;-   4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2-fluoropyridine;-   (2R,5R)-1-(4-chloro-3-fluorophenyl)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidine;-   1-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-4,4-difluoropiperidine;-   1-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-4-fluoropiperidine;-   1-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)piperidine;-   (2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)-1-(4-fluorophenyl)pyrrolidine;-   (2R,5R)-1-(4-tert-butylphenyl)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidine;-   (2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)-1-(4-cyclopropyl-3,5-difluorophenyl)pyrrolidine;-   (2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)-1-(4-cyclohexyl-3-fluorophenyl)pyrrolidine;-   (2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)-1-(3,4-difluorophenyl)pyrrolidine;-   (2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)-1-(4-(2,2-difluoroethoxy)phenyl)pyrrolidine;-   1-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-3,5-dimethylpiperidine;-   (2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)-1-[4-(pentafluoro-λ⁶-sulfanyl)phenyl]pyrrolidine    (ACD Name v12);-   2-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)phenyl)pyridine;-   (2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)-1-(3-chloro-4-(trifluoromethoxy)phenyl)pyrrolidine;-   (2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)-1-(4-(2-methoxyethoxy)-3-methylphenyl)pyrrolidine;-   (2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)-1-(4-chlorophenyl)pyrrolidine;-   (2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)-1-(4-((3-ethyloxetan-3-yl)methoxy)phenyl)pyrrolidine;-   (2R,5R)-1-(biphenyl-4-yl)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidine;-   (2R,5R)-1-(4-(1,3-dioxan-5-yloxy)phenyl)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidine;-   (2R,5R)-1-(4-((1,3-dioxolan-4-yl)methoxy)phenyl)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidine;-   (2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)-1-(4-((3-ethyloxetan-3-yl)methoxy)-3,5-difluorophenyl)pyrrolidine;-   1-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,3,5,6-tetrafluorophenyl)piperidine;-   1-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2-methylphenyl)piperidine;-   (3aR,7aS)-2-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)octahydro-1H-isoindole;-   4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-N-tert-butyl-2-fluoroaniline;-   1-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-4-methylpiperidine;-   (2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)-1-(4-(cyclopentyloxy)-3-fluorophenyl)pyrrolidine;-   (2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)-1-(3-fluoro-4-(methylthio)phenyl)pyrrolidine-   1-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,6-dichlorophenyl)piperidine;-   1-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,5-difluorophenyl)piperidine;-   (2R,6S)-1-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-2,6-dimethylpiperidine;-   1-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,3,6-trifluorophenyl)piperidine;-   (2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)-1-(4-cyclopropylphenyl)pyrrolidine;-   (1R,5S)-3-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-3-azabicyclo[3.2.0]heptane;-   (2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)-1-(4-cyclopropyl-2-fluorophenyl)pyrrolidine;-   1-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2-fluorophenyl)piperidine;-   1-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)phenyl)-4-phenylpiperidine;-   3-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-3-azaspiro[5.5]undecane;-   2-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)isoindoline;-   8-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-1,4-dioxa-8-azaspiro[4.5]decane;-   1-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-4-phenyl-1,2,3,6-tetrahydropyridine;-   1-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-4,4-diphenylpiperidine;-   1-(1-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-4-phenylpiperidin-4-yl)ethanone;-   1-(4-((2R,5R)-2,5-bis(4-chloro-2-fluoro-5-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)piperidine;-   1-(4-(2,5-bis(4-chloro-2-fluoro-5-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)piperidine;-   1-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-4-(3-phenylpropyl)piperidine;-   8-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-8-azaspiro[4.5]decane;-   1-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-4-(naphthalen-2-yl)piperidine;-   2-(1-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)piperidin-4-yl)pyridine;-   1-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-4-(4-(trimethylsilyl)phenyl)piperidine;-   1-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-4-(naphthalen-1-yl)piperidine;-   1-(4-((2R,5R)-2,5-bis(4-chloro-2-fluoro-5-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-4-(3-phenylpropyl)piperidine;-   6-(4-((2R,5R)-2,5-bis(4-chloro-2-fluoro-5-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-6-azaspiro[2.5]octane;-   1-(4-((2R,5R)-2,5-bis(4-chloro-2-fluoro-5-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-4-tert-butylpiperidine;-   1-(4-((2R,5R)-2,5-bis(4-chloro-2-fluoro-5-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-4-(naphthalen-2-yl)piperidine;-   1-(4-((2R,5R)-2,5-bis(4-chloro-2-fluoro-5-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-3,5-dimethylpiperidine;-   1′-(4-((2R,5R)-2,5-bis(4-chloro-2-fluoro-5-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-2,3-dihydrospiro[indene-1,4′-piperidine];-   1-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-3-phenylpiperidine;-   (2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)-1-(3,5-difluoro-4-(3-phenylpyrrolidin-1-yl)phenyl)pyrrolidine;-   1-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-4-(4-methoxyphenyl)piperidine;-   1-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-4-fluoro-4-phenylpiperidine;-   1-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)phenyl)-4-fluoro-4-phenylpiperidine;-   1-(4-((2R,5R)-2,5-bis(4-chloro-2-fluoro-5-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-4-(fluorodiphenylmethyl)piperidine;-   1-(4-((2R,5R)-2,5-bis(4-chloro-2-fluoro-5-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-4-phenylpiperidine;-   1-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-4-(4-fluorophenyl)piperidine;-   1-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-4-(3,4-difluorophenyl)piperidine;-   1-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-4-(3,5-difluorophenyl)piperidine;-   1-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-4-(3-(trimethylsilyl)phenyl)piperidine;-   (2R,5R)-1-(4-(benzyloxy)phenyl)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidine;-   1-(4-((2R,5R)-2,5-bis(4-chloro-2-fluoro-5-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-4-(4-(trifluoromethyl)phenyl)piperazine;-   1-(4-((2R,5R)-2-(4-chloro-2-fluoro-5-nitrophenyl)-5-(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)piperidine;-   4-benzyl-1-(4-((2R,5R)-2,5-bis(4-chloro-2-fluoro-5-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)piperidine;-   4-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-2-phenylmorpholine;-   1-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-2-phenylpiperidine;-   (2S,6R)-4-(4-((2R,5R)-2,5-bis(4-chloro-2-fluoro-5-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-2,6-dimethylmorpholine;-   3-(4-((2R,5R)-2,5-bis(4-chloro-2-fluoro-5-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-3-azaspiro[5,5]undecane;-   1-(4-((2R,5R)-2,5-bis(4-chloro-2-fluoro-5-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-4-cyclohexylpiperidine;-   (S)-4-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-2-phenylmorpholine;-   1-(4-((2R,5R)-2,5-bis(4-chloro-2-fluoro-5-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-4-(2,4-difluorophenyl)piperidine;-   1-(4-((2R,5R)-2,5-bis(4-chloro-2-fluoro-5-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-4-(4-fluorophenyl)piperidine;-   1-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-4-phenylpiperazine;-   1-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-4-(4-(trifluoromethyl)phenyl)piperazine;-   1-(4-((2R,5R)-2,5-bis(4-chloro-2-fluoro-5-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-4-(2,6-difluorophenyl)piperazine;-   2-(4-(4-((2R,5R)-2,5-bis(4-chloro-2-fluoro-5-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)piperazin-1-yl)pyrimidine;-   5-((2S,5R)-2,5-bis(4-chloro-2-fluoro-5-nitrophenyl)pyrrolidin-1-yl)-2-(4-phenylpiperidin-1-yl)pyrimidine;-   5-((2S,5R)-2,5-bis(4-chloro-2-fluoro-5-nitrophenyl)pyrrolidin-1-yl)-2-(piperidin-1-yl)pyrimidine;-   1-(4-((2S,5S)-2,5-bis(4-chloro-2-fluoro-5-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-4-(2,6-difluorophenyl)piperazine;-   1-(4-((2R,5R)-2,5-bis(4-chloro-2-fluoro-5-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-4-(5-methylthiophen-2-yl)piperidine;    and-   1-(4-((2R,5R)-2,5-bis(4-chloro-2-fluoro-5-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-4-fluoro-4-phenylpiperidine.

General Procedure 5. Nitro Reduction

Compounds (6) (1 equivalent) can be reduced to (7) by reaction with ironpowder (about 6 equivalents) and ammonium chloride (about 3 equivalents)in a solvent of THF:ethanol:water (1:1:0.2) with heating to about 60-80°C. The reaction can be worked up by cooling, filtering throughdiatomaceous earth, washing with ethanol and concentrating in vacuo.Alternatively, (6) (1 equivalent) can be reduced to (7) by hydrogenation(30 psi H₂) in the presence of PtO₂ (about 0.4 equivalents) in a solventof ethanol:THF (about 1:1). The reaction can be worked up by filtrationand evaporation of solvent. Alternatively, the reduction of (6) (1equivalent) to (7) can be effected by exposure to 30 psig hydrogen gasin the presence of Raney-nickel Grace 2800 (50% by weight of reactant)in a solvent such as tetrahydrofuran with shaking. The reaction can beworked up by filtration and evaporation of solvent. The product (7) canbe purified by chromatography over silica gel using typical organicsolvents including mixtures of ethyl acetate and hexane.

General Procedure 5.1. Nitro Reduction for Pyrrole

Compounds (11) can be converted to (12) using the conditions describedgenerally for General Procedure 5, particularly through the ironreduction method.

Illustration of General Procedure 5.1: General Procedure 5.1A

4,4′-(1-(4-Fluorophenyl)-1H-pyrrole-2,5-diyl)dianiline

To a solution of 1-(4-fluorophenyl)-2,5-bis(4-nitrophenyl)-1H-pyrrole(1.017 g, 2.496 mmol) in ethanol (15 mL) and THF (15 mL) was added ironpowder (0.836 g, 14.98 mmol) followed by ammonium chloride (0.401 g,7.49 mmol) and water (3.75 mL). The reaction mixture was refluxed for 45minutes. The reaction mixture was slurry filtered through diatomaceousearth and washed with ethanol. The combined filtrates were concentrated,and the residue purified by column chromatography (gradient elution from30% to 50% EtOAc:hexanes) to provide 1.09 g (77%) of the title compound.

General Procedure 6. Amide Coupling

Compounds (7) (1 equivalent) can be converted to compounds (8) byreaction with 1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid(about 2.5 equivalents) and HATU (about 2 to 3 equivalents) in thepresence of diisopropylethylamine (3-4 equivalents) in DMSO at aboutroom temperature. Alternatively to using HATU, this reaction can bepromoted using T3P or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide/1-hydroxybenzotriazole. The reaction can also be conductedin solvents such as tetrahydrofuran, ethyl acetate, or DMF. The reactioncan be worked up by partitioning between an organic solvent (e.g., ethylacetate) and water or dilute aqueous HCl, followed by separation of theorganic layer, optional washing of the organic with water and/or brine,drying the organic layer with a drying agent (e.g., MgSO₄, Na₂SO₄),filtration and evaporation of solvent. The product (8) can be purifiedby column chromatography over silica gel, eluting with standard organicsolvents including mixtures of ethyl acetate and hexane.

General Procedure 6.1. Amide coupling for pyrroles

Aniline compounds (12) can be converted to amides (13) using theconditions described generally above in General Procedure 6.

Illustration of General Procedure 6.1: General Procedure 6.1A

(2S,2′S)-tert-butyl2,2′-(4,4′-(1-(4-tert-butylphenyl)-1H-pyrrole-2,5-diyl)bis(4,1-phenylene)bis(azanediyl)bis(oxomethylene))dipyrrolidine-1-carboxylate

To a solution of4,4′-(1-(4-tert-butylphenyl)-1H-pyrrole-2,5-diyl)dianiline (0.310 g,0.813 mmol) in DMF (5 mL) was added(S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (0.385 g, 1.79mmol) 1-hydroxybenzotriazole hydrate (0.274 g; 1.79 mmol) andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.343 g,1.79 mmol), and the mixture stirred overnight. The mixture was pouredinto water and extracted CH₂Cl₂. The organic extract was dried (Na₂SO₄),filtered and concentrated to give a crude product that was purified bytrituration with ether to give 325 mg (51%) of the title compound. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.25 (s, 24H) 1.83 (s, 6H) 2.15 (s, 2H)3.45 (m, 4H) 4.18 (s, 2H) 6.40 (s, 2H) 6.98 (s, 6H) 7.37 (s, 6H) 9.98(s, 2H).

General Procedure 7. Suzuki Coupling

Dibromo compounds (34.1) (1 equivalent) can be converted to diboronatecompounds (35.1) by mixing with bis(pinacolato)diborane (about 2 to 4equivalents), potassium acetate (about 4-8 equivalents), and1,1′-bis(diphenylphosphino)ferrocene-palladium(II) chloridedichloromethane complex (PdCl₂(dppf)) (about 0.1 to 0.2 equivalents) ina solvent such as DME, dioxane, or DMSO, degassing the mixture andheating to about 85° C. The reaction can be worked up by cooling to roomtemperature, diluting with methylene chloride, optionally washing theorganics with water and/or brine, drying the organics with a dryingagent (e.g., MgSO₄, Na₂SO₄), filtration and evaporation of solvent.Compounds (35.1) can be converted to compounds (36.1) by mixing withIntermediate 1D (about 1 to 2 equivalents), aqueous sodium carbonatesolution (about 1 to 3.5 equivalents), and PdCl₂(dppf) (about 0.03 to0.2 equivalents) in a solvent like dimethoxyethane or toluene:ethanol(1:1), degassing, and heating the reaction to around 80-100° C. Thereaction can be worked up by cooling to room temperature, partitioningbetween an organic solvent (e.g., ethyl acetate) and water, optionallywashing the organics with water and/or brine, drying the organics with adrying agent (e.g., MgSO₄, Na₂SO₄), filtration and evaporation ofsolvent. Alternatively, the reaction can be worked up by concentrationin vacuo, partitioning between 25% isopropylalcohol/chloroform, dryingthe organics (e.g., Na₂SO₄), filtration, and evaporation of the solvent.Compounds (35.1) and (36.1) can be purified by column chromatographyover silica gel, eluting with standard organic solvents includingmixtures of ethyl acetate and hexane; or purified by trituration orrecrystallization.

Illustration of General Procedure 7: General Procedure 7A

racemictrans-1-(4-tert-butylphenyl)-2,5-bis(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine

Racemic trans-2,5-bis(4-bromophenyl)-1-(4-tert-butylphenyl)pyrrolidine(3.88 g, 7.56 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (6.72 g,26.5 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)(0.617 g, 0.756 mmol), and potassium acetate (3.34 g, 34.0 mmol) werecombined in dimethoxyethane (70 mL) and nitrogen gas was sparged throughthe solution for 10 minutes. The reaction mixture was then heated at 85°C. for 1 hour. The reaction solution was cooled to room temperature,filtered through diatomaceous earth and washed with ethyl acetate (20mL). The filtrate was dried and concentrated, and the residue waspurified by column chromatography on silica gel, eluting with a solventgradient of 0-10% ethyl acetate in hexane followed by trituration of theresultant solid with diethyl ether to give the title compound (1.14 g,25%) as a 1/1 mixture of trans stereoisomers.

(2S,2′S)-tert-butyl2,2′-(5,5′-(4,4′-(1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(4,1-phenylene))bis(1H-imidazole-5,2-diyl))dipyrrolidine-1-carboxylate

Racemictrans-1-(4-tert-butylphenyl)-2,5-bis(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine(0.915 g, 1.506 mmol), Intermediate 1D (1.429 g, 4.52 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.123 g,0.151 mmol) were dissolved in a mixture of toluene (7 mL), ethanol (7mL) and a 2 N aq. sodium bicarbonate solution (2.64 mL, 5.28 mmol).Nitrogen gas was bubbled through the solution for 10 minutes, and thenthe reaction mixture was heated at 100° C. for 3 hours. The reactionsolution was cooled to room temperature and water (20 mL) was added.Then the reaction mixture was extracted with dichloromethane (50 mL),dried, and concentrated. The residue was purified by columnchromatography on silica gel eluting with a solvent gradient of 0-80%ethyl acetate in hexane to give the title compound (0.93 g, 75%) as a1/1 mixture of trans stereoisomers.

General Procedure 7.1. Suzuki Coupling for Pyrroles

Dibromo compounds (46) can be converted sequentially to compounds (47)and (43) using the conditions described generally above in GeneralProcedure 7.

Illustration of General Procedure 7.1: General Procedure 7.1B

1-(4-tert-butylphenyl)-2,5-bis(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrrole

To a solution of2,5-bis(4-bromophenyl)-1-(4-tert-butylphenyl)-1H-pyrrole (2.32 g, 4.56mmol) in DMSO (26 mL) at room temperature were addedbis(pinacolato)diborane (2.54 g, 10.02 mmol), potassium acetate (5.00 g,36.4 mmol) and PdCl₂(dppf) (744 mg, 0.91 mmol). The mixture was degassedand heated to 85° C. After 4 hours, the mixture was cooled to roomtemperature, diluted with dichloromethane and washed with water followedby brine. The organic phase was dried (Na₂SO₄) and concentrated. Theresidue was taken up in 20% ethyl acetate/hexanes and filtered through ashort plug of silica gel (elution with 20% ethyl acetate:hexanes) andconcentrated to afford the title compound as a light yellow solid (1.62g; 59% yield).

(2S,2′S)-tert-butyl2,2′-(4,4′-(4,4′-(1-(4-tert-butylphenyl)-1H-pyrrole-2,5-diyl)bis(4,1-phenylene))bis(1H-imidazole-4,2-diyl))dipyrrolidine-1-carboxylate

A mixture of Intermediate 1D (664 mg, 2.10 mmol),1-(4-tert-butylphenyl)-2,5-bis(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrrole(1.48 g, 2.45 mmol), 2 M sodium carbonate (1400 μL, 2.80 mmol), andPd(dppf)Cl₂ (51.2 mg, 0.070 mmol) in DME (2800 μL) was subjected tomicrowave irradiation at 140° C. for 20 minutes. The mixture was dilutedwith ethyl acetate, then washed with water and brine, and dried overNa₂SO₄. The product was purified on silica gel eluting with 30 to 70%ethyl acetate:hexanes to provide the title compound (140 mg; 24% yield).

General Procedure 8. Buchwald Reaction

Compounds (64) (1 equivalent) can be converted to compounds (65) bymixing with tert-butyl 2-carbamoylpyrrolidine-1-carboxylate (about 3equivalents), cesium carbonate (about 3 equivalents),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (about 0.05 to 0.3equivalents), and tris(dibenzylideneacetone)dipalladium(0) (about 0.05to 0.2 equivalents) in dioxane, degassing the mixture, and heating toaround 100° C. for between about 1 to 8 hours. Alternatively, thereaction can be conducted using potassium carbonate (about 3equivalents), Pd(OAc)₂ (about 0.02 equivalents), and4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (about 0.04equivalents). The reaction can be conducted in a flask with a refluxcondenser under inert atmosphere or in a sealed tube. The products (65)can be purified by silica gel chromatography eluting with standardsolvents including ethyl acetate and methylene chloride.

Illustration of General Procedure 8: General Procedure 8A

(2S,2′S)-tert-butyl2,2′-(4,4′-((2R,5R)-1-(4-cyclohexylphenyl)pyrrolidine-2,5-diyl)bis(2-nitro-4,1-phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-1-carboxylate

(2R,5R)-2,5-Bis(4-chloro-3-nitrophenyl)-1-(4-cyclohexylphenyl)pyrrolidine(General Procedure 4A) (1.29 g, 2.39 mmol), (S)-tert-butyl2-carbamoylpyrrolidine-1-carboxylate (1.53 g, 7.16 mmol), cesiumcarbonate (2.33 g, 7.16 mmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.33 g, 0.573 mmol),and tris(dibenzylideneacetone)dipalladium(0) (0.328 g, 0.358 mmol) werecombined in dioxane (18 mL) and nitrogen was bubbled through thesolution for 15 minutes. Then the flask was capped with a refluxcondenser and the solution was heated at 100° C. for 8 hours. Afterfiltering through diatomaceous earth and concentrating, the residue waspurified with a CombiFlash® 80 g silica column, eluting with 0-20% ethylacetate in dichloromethane to give 1.71 g (80%) of the title compound.

Illustration of General Procedure 8: General Procedure 8B, Example 1A

(2S,2′S)-tert-butyl2,2′-(4,4′-((2R,5R)-1-(3,5-difluoro-4-(4-phenylpiperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-nitro-4,1-phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-1-carboxylate

To a 100 mL round-bottomed flask was added1-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-4-phenylpiperidine(2.26 g, 3.46 mmol), (S)-tert-butyl 2-carbamoylpyrrolidine-1-carboxylate(2.223 g, 10.37 mmol), cesium carbonate (3.38 g, 10.37 mmol),tris(dibenzylideneacetone)dipalladium(0) (0.190 g, 0.207 mmol) and(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.300 g,0.519 mmol) in dioxane (34.6 mL) to give a purple suspension. Themixture was sparged with N₂ for 20 minutes, heated under N₂ at 100° C.for 3 hours, cooled and poured into EtOAc. The EtOAc layer was washed2×50 mL with H₂O and then with saturated NaCl. The EtOAc layer wastreated simultaneously for 1 hour with 3-mercaptopropyl silica andNa₂SO₄, filtered and concentrated. Purification using chromatography ona 120 g silica cartridge eluting with 1-3% methanol in methylenechloride gave material that was 90% pure by HPLC. A second column on a120 g silica cartridge eluting with 15-50% EtOAc in hexane provided thetitle compound as an orange foam (2.6 g, 72%, 97% purity by HPLC). MS(ESI+) m/z 1009 (M+H)⁺.

Illustration of General Procedure 8: General Procedure 8B, Example 1B(Mono-Displacement)methyl(S)-1-((S)-2-(4-((2R,5R)-5-(4-chloro-3-nitrophenyl)-1-(3,5-difluoro-4-(4-phenylpiperidin-1-yl)phenyl)pyrrolidin-2-yl)-2-nitrophenylcarbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

1-(4-((2R,5R)-2,5-Bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-4-phenylpiperidine(0.745 g, 1.14 mmol) was dissolved in dioxane (12 mL) in a tube andtreated withmethyl(S)-1-((S)-2-carbamoylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(0.309 g, 1.14 mmol), cesium carbonate (0.409 g, 1.25 mmol), Xantphos(0.066 g, 0.11 mmol), and tris(dibenzylideneacetone)dipalladium(0)(0.052 g, 0.057 mmol). Nitrogen was bubbled through this mixture for 15minutes, then the tube was sealed and heated at 100° C. for 2 hours. Themixture was diluted with water, extracted into dichloromethane,concentrated, and purified by chromatography, eluting with 0-5% methanolin dichloromethane to give 0.44 g (43%) of a dark yellow solid.

Illustration of General Procedure 8: General Procedure 8B, Example 2

tert-butyl2,2′-(4,4′-((2R,5R)-1-(3,5-difluoro-4-(piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-2-nitro-4,1-phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-1-carboxylate

To a round bottom flask was combined1-(4-((2R,5R)-2,5-bis(4-chloro-2-fluoro-5-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)piperidine(4.1 g, 6.68 mmol), (S)-tert-butyl 2-carbamoylpyrrolidine-1-carboxylate(4.30 g, 20.05 mmol), cesium carbonate (6.1 g, 18.72 mmol), and XantPhos(0.696 g, 1.203 mmol) followed by dioxane (30 ml) and the solution wasde-gassed with N₂ gas for 30 minutes. The solution was stirredvigorously to keep the solids mixing and kept the flow rate of N₂ gas ata high rate to ensure complete de-gassing of the mixture.Tris(dibenzylideneacetone)dipalladium (0.367 g, 0.401 mmol) was addedand the solution heated at 100° C. for 2 hours under N₂ gas. Thesolution was cooled and diluted with EtOAc, filtered throughdiatomaceous earth, washed with H₂O and brine, dried (Na₂SO₄), filtered,treated for 30 minutes with 3-mercaptopropyl-functionalized silica gel,filtered and concentrated to give crude product. Purification was run onan ISCO 120 g silica gel cartridge eluting with 0-40% EtOAc/hexane over30 minutes to give the title compound (4.52 g, 4.66 mmol, 69.8%).

General Procedure 8.1. Buchwald with Dipeptide

dimethyl(2R,2′R)-1,1′-((2S,2′S)-2,2′-(4,4′-1-(3-fluoro-4-morpholinophenyl)pyrrolidin-2,5-diyl)bis(2-nitro-4,1-phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate

In a microwave tube, a suspension of4-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2-fluorophenyl)morpholine(1.39 g, 2.48 mmoL), Intermediate 3B (2.02 g, 7.43 mmol), XantPhos (129mg, 0.22 mmol) and cesium carbonate (2.42 g, 7.43 mmoL) in dioxane (14mL) was degassed by nitrogen sparge for 30 minutes. The mixture wastreated with tris(dibenzylideneacetone)dipalladium (0) (68 mg, 0.074mmol) followed by degassing for another 5 minutes. The microwave tubewas sealed and the mixture was warmed at 100° C. for 2 hours. Themixture was cooled and diluted with ethyl acetate and extracted withwater (3×) and saturated sodium chloride solution. The solution wasdried (Na₂SO₄) and stirred overnight with 3-(mercaptopropyl) silica gel.Filtration and concentration in vacuo afforded a solid which waschromatographed over a 340 g silica gel cartridge, eluting with 0-10%methanol in dichloromethane. These procedures afforded the titlecompound as an orange solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.80-0.90(m, 12H) 1.74 (br s, 2H) 1.82-2.03 (m, 10H) 2.08-2.20 (m, 2H) 2.71-2.81(m, 4H) 3.52 (s, 6H) 3.62 (m, 4H) 3.76 (s, 2H) 4.02 (m, 2H) 4.50 (d,J=4.4 Hz, 2H) 5.39 (s, 2H) 6.04-6.19 (m, 2H) 6.74f6.81 (m, 1H) 7.32 (d,J=8.4 Hz, 2H) 7.47-7.60 (m, 4H) 7.80 (d, J=1.5 Hz, 2H) 10.41 (s, 2H); MS(ESI) m/z 1031 (M+H)⁺.

General Procedure 9. Nitro Reduction

Compounds (65) (1 equivalent) can be converted to compounds (66) byhydrogenation with hydrogen gas (1-4 atm) over a catalyst such as PtO₂(about 0.2 to 0.3 equivalents) or Raney-nickel (e.g., 50% aqueous; 1equivalent by weight) in solvents such as tetrahydrofuran, ethanol, ormixtures thereof. The reaction can be worked up by filtration throughdiatomaceous earth or silica gel, and the filtrate concentrated to givecompounds (66). Reduction of (65) (1 equivalent) can also be effected byreaction with iron powder (about 6 equivalents) and ammonium chloride(about 3 equivalents) in a solvent of THF:ethanol:water (1:1:0.2) withheating to about 60-100° C.

Illustration of General Procedure 9: General Procedure 9A, Example 1

(2S,2′S)-tert-butyl2,2′-(4,4′-((2R,5R)-1-(4-(4-phenylpiperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-amino-4,1-phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-1-carboxylate

A solution of (2S,2′S)-tert-butyl2,2′-(4,4′-((2R,5R)-1-(4-(4-phenylpiperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-nitro-4,1-phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-1-carboxylate(2.287 g, 2.350 mmol) in THF (60 mL) was added to PtO₂ (0.457 g, 2.014mmol) in a 250 mL stainless steel pressure bottle and stirred for 4hours at room temperature under 30 psi hydrogen pressure. The mixturewas then filtered through a nylon membrane and the filtrate concentratedby rotary evaporation and dried in vacuo to give the title compound as abrown solid (2.02 g, 94%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.30-1.44 (m,18H), 1.53-1.98 (m, 11H), 2.08-2.29 (m, 1H), 2.43-2.60 (m, 3H),3.35-3.50 (m, 4H), 4.16-4.29 (m, 2H), 4.79 (d, J=35.46 Hz, 4H), 4.97 (s,2H), 6.21 (d, J=8.89 Hz, 2H), 6.41 (dd, J=20.66, 7.86 Hz, 2H), 6.53-6.61(m, 2H), 6.66 (d, J=8.89 Hz, 2H), 6.93-7.06 (m, 2H), 7.17 (t, J=6.89 Hz,1H), 7.21-7.32 (m, 4H), 9.18 (d, J=39.25 Hz, 2H); MS (ESI+) m/z 913(M+H)⁺; MS (ESI−) m/z 911 (M−H)⁻.

Illustration of General Procedure 9: General Procedure 9A, Example 2tert-butyl2,2′-(4,4′-((2R,5R)-1-(3,5-difluoro-4-(piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-amino-5-fluoro-4,1-phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-1-carboxylate

tert-Butyl2,2′-(4,4′-((2R,5R)-1-(3,5-difluoro-4-(piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-2-nitro-4,1-phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-1-carboxylate(4.5 g, 4.64 mmol) and THF (100 ml) were added to PtO₂ (0.900 g, 3.96mmol) in a 250 ml stainless steel pressure bottle and stirred for 22hours under a hydrogen atmosphere (30 psi) at room temperature. Themixture was filtered through a nylon membrane and concentrated to ayellow-orange foam.

Illustration of General Procedure 9: General Procedure 9B

(2S,2′S)-tert-butyl2,2′-(4,4′-((2R,5R)-1-(3,5-difluoro-4-(4-phenylpiperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-amino-4,1-phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-1-carboxylate

In a 250 mL pressure bottle were combined (2S,2′S)-tert-butyl2,2′-(4,4′-((2R,5R)-1-(3,5-difluoro-4-(4-phenylpiperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-nitro-4,1-phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-1-carboxylate(General Procedure 8B) (2.6 g, 2.58 mmol) and Raney-nickel 2800 (45% w/win water, 2.6 g, 44 mmol) in THF (40 mL). The vessel was sealed andstirred under 30 psi H₂ for 5 hours. The solution was filtered through anylon membrane and the filtrate was concentrated to afford the titlecompound as a tan foam (2.44 g, quantitative yield) that was usedwithout purification. MS (ESI+) m/z 949 (M+H)⁺.

Illustration of General Procedure 9: General Procedure 9C

dimethyl([(2R,5R)-1-(4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)pyrrolidine-2,5-diyl]bis{(2-aminobenzene-4,1-diyl)carbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-1-oxobutane-1,2-diyl]})biscarbamate (ACD Name v12))

Dimethyl([(2R,5R)-1-(4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)pyrrolidine-2,5-diyl]bis{(2-nitrobenzene-4,1-diyl)carbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-1-oxobutane-1,2-diyl]})biscarbamate(ACD Name v12)) (0.59 g, 0:596 mmol) was dissolved in tetrahydrofuran(15 mL) and treated with Raney-nickel slurry in water (0.25 mL). Theflask was evacuated and opened to a hydrogen balloon and stirred atambient temperature for 1 hour. The solution was filtered through asilica plug and concentrated to dryness to give the title compound.

Illustration of General Procedure 9: General Procedure 9D

dimethyl(2S,2′S)-1,1′-((2S,2′S)-2,2′-(4,4′-((2R,5R)-1-(4-chloro-3-fluorophenyl)pyrrolidine-2,5-diyl)bis(2-amino-4,1-phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate

Dimethyl(2S,2′S)-1,1′-((2S,2′S)-2,2′-(4,4′-((2R,5R)-1-(4-chloro-3-fluorophenyl)pyrrolidine-2,5-diyl)bis(2-nitro-4,1-phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate(1.0 g, 1.02 mmol) and tetrahydrofuran (25 mL) were added to platinumoxide (0.20 g, 0.88 mmol) in a pressure bottle and stirred at ambienttemperature under hydrogen at 30 psi for 1.5 hours. The solution wasfiltered through a nylon membrane and concentrated to dryness to give100% yield of a brown residue that was used without purification.

Illustration of General Procedure 9: General Procedure 9E

dimethyl(2S,2′S)-1,1′-((2S,2′S)-2,2′-(4,4′-((2R,5R)-1-(3,5-difluoro-4-(4-phenyl-5,6-dihydropyridin-1(2H)-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-amino-4,1-phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate

Dimethyl(2S,2′S)-1,1′-((2S,2′S)-2,2′-(4,4′-((2R,5R)-1-(3,5-difluoro-4-(4-phenyl-5,6-dihydropyridin-1(2H)-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-nitro-4,1-phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate(150 mg, 0.134 mmol) was dissolved in a mixture of THF (1 mL) andabsolute EtOH (1 mL) under nitrogen. A solution of ammonium chloride(10.73 mg, 0.201 mmol) in water (0.333 mL), followed by iron powder(37.4 mg, 0.669 mmol) was added, and the mixture was heated under areflux condenser in an oil bath at 90° C. After 1 hour, the reactionmixture was cooled to room temperature, vacuum filtered through a bed ofCelite 545, and washed thoroughly with EtOAc. The filtrate wasconcentrated by rotary evaporation to remove the organic solvents. Theresidue was dissolved in EtOAc (50 mL), washed with water (2×25 mL) andbrine (25 mL), dried over anhydrous MgSO₄, filtered, and concentrated byrotary evaporation. The residue was purified by SiO₂ flashchromatography (Alltech Extract-Clean column, 10 g bed) eluting with astep gradient of 3% to 4% methanol/CH₂Cl₂ to afford the product as ayellow solid (77 mg, 0.073 mmol, 54%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm0.92 (dd, J=13.07, 6.56 Hz, 12H), 1.58-1.75 (m, 2H), 1.83-2.09 (m, 8H),2.13-2.28 (m, 1H), 3.17 (s, 2H), 3.38-3.68 (m, 8H), 3.55 (s, 6H), 3.84(s, 2H), 4.05 (t, J=8.35 Hz, 2H), 4.37-4.47 (m, 2H), 4.93 (s, 4H), 5.01(d, J=5.10 Hz, 2H), 5.85-6.00 (m, 2H), 6.14 (s, 1 H), 6.44 (d, J=8.02Hz, 2H), 6.55-6.66 (m, 2H), 7.02 (d, J=7.81 Hz, 2H), 7.21-7.49 (m, 8H),9.28 (s, 2H); MS (ESI+) m/z 1061 (M+H)⁺; MS (ESI−) m/z 1059 (M−H)⁻.

General Procedure 10. Benzimidazole Formation

Compounds (66) can be converted to compounds (57) by heating neat inacetic acid or with acetic acid in toluene or dioxane at 50-80° C. Thereaction can be worked up by concentrating the solution, neutralizingwith aqueous sodium bicarbonate solution, extracting with an organicsolvent (e.g., dichloromethane), drying the organic solvent mixture(e.g., MgSO₄, Na₂SO₄), filtering and concentrating in vacuo. Thereaction can also be conducted in toluene as solvent with added aceticacid (about 3 to 5 equivalents) also with heating to 50-80° C. Workupcan consist of simple solvent evaporation and the removal of residualacetic acid by the addition and evaporation of toluene. Compounds (57)can be purified by chromatography over silica gel eluting with ethylacetate/dichloromethane or methanol/dichloromethane. Although thecyclization depicted above is shown with a t-butoxycarbonyl (Boc) groupattached, the reaction can also be conducted with the groups -T—R_(D)attached, wherein T and R_(D) are as defined herein.

Illustration of General Procedure 10: General Procedure 10A; Example 1

(2S,2′S)-tert-butyl2,2′-(5,5′-(1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(1H-benzo[d]imidazole-5,2-diyl))dipyrrolidine-1-carboxylate

As a mixture of trans diastereomers, (2S,2′S)-tert-butyl2,2′-(5,5′-(1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(2-amino-5,1-phenylene)bis(azanediyl)bis(oxomethylene))dipyrrolidine-1-carboxylate(0.355 g) was dissolved in neat acetic acid (3 mL) and heated at 72° C.for 2 hours. The solution was concentrated and then poured into waterwhere the pH was adjusted to ˜7-8 with sodium bicarbonate. The productwas extracted into dichloromethane, concentrated and purified bychromatography on silica gel with a 40 g column, eluting with 0-5%methanol/dichloromethane to give 0.185 g (55%) of the title compound asa light yellow solid.

Illustration of General Procedure 10: General Procedure 10A; Example 2

(2S,2′S)-tert-butyl2,2′-(6,6′-((2R,5R)-1-(3,5-difluoro-4-(4-phenylpiperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(1H-benzo[d]imidazole-6,2-diyl))dipyrrolidine-1-carboxylate

A solution of (2S,2′S)-tert-butyl2,2′-(4,4′-((2R,5R)-1-(3,5-difluoro-4-(4-phenylpiperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-amino-4,1-phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-1-carboxylate(2.4 g, 2.57 mmol) and acetic acid (1.54 g, 25.7 mmol) in toluene (50mL) was heated at 70° C. for 2 hours, cooled and concentrated. Theresidue was azeotroped 3×15 mL with toluene and dried under vacuum togive a yellow foam (2.34 g, quantitative yield) that was used withoutpurification. MS (ESI+) m/z 913 (M+H)⁺.

Illustration of General Procedure 10: General Procedure 10A; Example 3(2S,2′S)-tert-butyl2,2′-(6,6′-((2R,5R)-1-(3,5-difluoro-4-(piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-1H-benzo[d]imidazole-6,2-diyl))dipyrrolidine-1-carboxylate

To crude tert-butyl2,2′-(4,4′-((2R,5R)-1-(3,5-difluoro-4-(piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-amino-5-fluoro-4,1-phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-1-carboxylate(from General Procedure 9A, Example 2) was added toluene (45 ml)followed by acetic acid (2.66 ml, 46.4 mmol) and the solution wasstirred at 50° C. for 16 hours. The cooled solution was concentrated,azeotroped twice with toluene, and the crude residue was purified on anISCO 40 g silica gel cartridge eluting with 0-5% CH₃OH/CH₂Cl₂ to givethe title compound (2.85 g).

Illustration of General Procedure 10: General Procedure 10B, Example 1

methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-(4-chloro-3-fluorophenyl)-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate(ACD Name v12)

Dimethyl(2S,2′S)-1,1′-((2S,2′S)-2,2′-(4,4′-((2R,5R)-1-(4-chloro-3-fluorophenyl)pyrrolidine-2,5-diyl)bis(2-amino-4,1-phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1-diyl)bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate(General Procedure 9D) (0.98 g, 1.01 mmol) was dissolved in toluene (12mL) and treated with glacial acetic acid (1.16 mL, 20.2 mmol) and heatedat 65° C. for 1.5 hours. The mixture was concentrated, dissolved indichloromethane, and washed with sodium bicarbonate solution. Theorganic reaction mixture was concentrated and purified bychromatography, eluting with 0-6% methanol in dichloromethane to give0.17 g (19%) of the title compound as a dark yellow solid. ¹H NMR (400MHz, DMSO-d₆) δ ppm 0.77-0.90 (m, 12H) 1.66-1.78 (m, 2H) 1.88-1.95 (m,2H) 1.96-2.06 (m, 4H) 2.15-2.24 (m, 4H) 2.54-2.60 (m, 2H) 3.54 (s, 6H)3.79-3.86 (m, 4H) 4.06 (t, J=8.46 Hz, 2H) 5.10-5.18 (m, 2H) 5.37-5.45(m, 2H) 6.16 (dd, J=9.49, 2.01 Hz, 1H) 6.22 (dd, J=13.55, 2.06 Hz, 1H)7.00-7.11 (m, 3H) 7.22 (s, 1H) 7.28 (d, J=8.57 Hz, 2H) 7.32 (s, 1H) 7.40(d, J=8.24 Hz, 1H) 7.47 (d, J=8.13 Hz, 1H) 12.07 (d, J=2.93 Hz, 2 H); MS(APCI+) m/z 884 (M+H)⁺.

Illustration of General Procedure 10: General Procedure 10B; Example 2

methyl{(2S)-1-[(2S)-2-{6-[(2R,5R)-1-[3-fluoro-4-(methylsulfonyl)phenyl]-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-6-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate(ACD Name v12)

To a suspension ofdimethyl(2S,2′S)-1,1′-((2S,2′S)-2,2′-(4,4′-((2R,5R)-1-(3-fluoro-4-(methylsulfonyl)phenyl)pyrrolidine-2,5-diyl)bis(2-amino-4,1-phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1-diyl)bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate(0.190 g, 0.197 mmol) in toluene (2 mL) was added acetic acid (1 mL,17.48 mmol), and the reaction mixture was stirred at 60° C. overnight.LCMS shows completion of reaction. The reaction mixture was diluted withethyl acetate and washed with a saturated solution of NaHCO₃. Theorganic extract was separated, dried over anhydrous sodium sulfate,filtered, concentrated on a rotovap and purified by reverse phase HPLCusing 5-100% acetonitrile/water(TFA). Pure fractions were combined,neutralized with saturated solution of NaHCO₃, and concentrated. Theresidue was extracted with CH₂Cl₂. The organic extract was separated,dried over anhydrous sodium sulfate, filtered, and concentrated tosupply the title compound (30 mg) as a white solid.

General Procedure 11. Procedure to Remove t-Butoxycarbonyl ProtectingGroups

Removal of a t-butoxycarbonyl (Boc) protecting group, according to theabove depiction can be effected using standard conditions such as bytreatment with an acid, such as TFA, HCl, or formic acid. For example,reaction with TFA/CH₂Cl₂ or HCl in dioxane at room temperature canremove the Boc protecting group. Compounds may be used or isolated asthe salt or free base.

After removal of the Boc-protecting groups and in cases where compoundshave been processed through as mixtures of cis,

and trans,

pyrrolidines, the cis and trans diastereomers may be subject toseparation using standard chromatographic methods (e.g., normal phasesilica gel or reverse phase). For example, compounds of general type11-1 and 11-2 can be separated in this manner.

Illustration of General Procedure 11. General Procedure 11A(HCl-Dioxane), Example 1

(S)-5,5′-(1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole)

(2S,2′S)-tert-Butyl2,2′-(5,5′-(1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(1H-benzo[d]imidazole-5,2-diyl))dipyrrolidine-1-carboxylate(0.204 g, 0.264 mmol) was dissolved in THF (2 mL) at room temperatureand treated with 4 M HCl in dioxane (2 mL). After completion of thereaction, the mixture was concentrated to dryness to provide the crudetitle compound.

Illustration of General Procedure II. General Procedure 11A(HCl-Dioxane), Example 2(S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(4-phenylpiperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole)

A solution of (2S,2′S)-tert-butyl2,2′-(6,6′-((2R,5R)-1-(3,5-difluoro-4-(4-phenylpiperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(1H-benzo[d]imidazole-6,2-diyl))dipyrrolidine-1-carboxylate(2.34 g, 2.57 mmol) in dioxane (25 mL) was treated with 4 M hydrogenchloride in dioxane (16.06 mL, 64.3 mmol) to give a tan suspension. Themixture was sonicated for 10 minutes to break up solids into a finesuspension, stirred for 2 hours and concentrated. The residue wasazeotroped 3×30 mL with toluene and dried to give the HCl salt of thetitle compound as a tan powder that was used without purification(assume quantitative yield, 2.57 mmol). MS (ESI+) m/z 713 (M+H)⁺.

Illustration of General Procedure 11. General Procedure 11A(HCl-Dioxane), Example 36,6′-{(2R,5R)-1-[3,5-difluoro-4-(piperidin-1-yl)phenyl]pyrrolidine-2,5-diyl}bis{5-fluoro-2-[(2S)-pyrrolidin-2-yl]-1H-benzimidazole}(ACD Name v12)

To a solution of (2S,2′S)-tert-butyl2,2′-(6,6′-((2R,5R)-1-(3,5-difluoro-4-(piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-1H-benzo[d]imidazole-6,2-diyl))dipyrrolidine-1-carboxylate(2.85 g, 3.26 mmol) in dioxane (10 ml) was added 4 M HCl/dioxane (10.0mL, 40.0 mmol) and the solution was vigorously stirred at roomtemperature for 1 hour. The solution was concentrated, dissolved inminimal H₂O and applied to an ISCO 130 g C18 cartridge and eluted with0-100% CH₃CN/(0.1% TFA/H₂O). Desired fractions were combined, made basicwith 10% NaHCO₃ solution, and extracted with EtOAc. The combinedextracts were dried (MgSO₄), filtered and concentrated to give the titlecompound (932.5 mg, 1.386 mmol, 42.5%).

Illustration of General Procedure 11. General Procedure 11B (TFA-CH₂Cl₂)

(S)-5,5′-(1-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole)

(2S,2′S)-tert-Butyl2,2′-(5,5′-(1-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(1H-benzo[d]imidazole-5,2-diyl))dipyrrolidine-1-carboxylate(0.120 g, 0.163 mmol) was dissolved in dichloromethane (2 mL) at roomtemperature and treated with TFA (1 mL). The mixture was concentrated todryness, dissolved in 25% isopropanol/dichloromethane and washed withsodium bicarbonate solution. The resulting solids were filtered off anddried. The organic filtrate was concentrated and dried to give the moretitle compound. The batches of off-white solid were combined to give thetitled compound (0.062 g 72% yield).

The following compounds as free base or salt can be made using GeneralProcedure 8, General Procedure 9A (PtO₂), General Procedure 10/10A, andGeneral Procedure 11/11A:

-   (S)-6,6′-((2R,5R)-1-(4-(pyridin-2-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(3-chloro-4-(trifluoromethoxy)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(4-(2-methoxyethoxy)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[c]imidazole);-   (S)-6,6′-((2R,5R)-1-(4-chlorophenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(3-methyl-4-(piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2S,5S)-1-(4-cyclopropyl-3,5-difluorophenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2S,5S)-1-(4-cyclopropyl-2-fluorophenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(3-fluoro-4-(piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(4-(4-tert-butylpiperidin-1-yl)-3,5-difluorophenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(4-(4,4-dimethylpiperidin-1-yl)-3,5-difluorophenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(6-azaspiro[2.5]octan-6-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(isoindolin-2-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   2-(4-((2R,5R)-2,5-bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)pyrrolidin-1-yl)-2,6-difluorophenyl)-2-azabicyclo[2.2.2]octane;-   (S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(4-isopropylpiperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(4-(3,3-dimethylazetidin-1-yl)-3,5-difluorophenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(4-(4-phenylpiperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   6,6′-{(2R,5R)-1-[3,5-difluoro-4-(piperidin-1-yl)phenyl]pyrrolidine-2,5-diyl}bis{5-fluoro-2-[(2S)-pyrrolidin-2-yl]-1H-benzimidazole}    (ACD Name v12);-   (S)-6,6′-((2S,5R)-1-(3,5-difluoro-4-(piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole)-   (S,S,S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-2-((2S,3aS,6aS)-octahydrocyclopenta[b]pyrrol-2-yl)-1H-benzo[d]imidazole);-   (S,S,S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((2S,3aS,6aS)-octahydrocyclopenta[b]pyrrol-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(4-(2,3-dihydrospiro[indene-1,4′-piperidine]-1′-yl)-3,5-difluorophenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(4-(4-methoxyphenyl)piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(4-fluoro-4-phenylpiperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(4-(4-fluoro-4-phenylpiperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(4-(fluorodiphenylmethyl)piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(4-phenylpiperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(4-(4-fluorophenyl)piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(4-(3-(trimethylsilyl)phenyl)piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(4-(4-(3,4-difluorophenyl)piperidin-1-yl)-3,5-difluorophenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(4-(4-(3,5-difluorophenyl)piperidin-1-yl)-3,5-difluorophenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   6-((2R,5R)-1-(3,5-difluoro-4-(piperidin-1-yl)phenyl)-5-(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)pyrrolidin-2-yl)-5-fluoro-2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole;-   (S)-6,6′-((2R,5R)-1-(4-(4-benzylpiperidin-1-yl)-3,5-difluorophenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(4-(4-benzylpiperidin-1-yl)-3,5-difluorophenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2S,5R)-1-(3,5-difluoro-4-(4-phenylpiperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   4-(4-((2R,5R)-2,5-bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)pyrrolidin-1-yl)-2,6-difluorophenyl)-2-phenylmorpholine;-   (S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(2-phenylpiperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (2S,6R)-4-(4-((2R,5R)-2,5-bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)pyrrolidin-1-yl)-2,6-difluorophenyl)-2,6-dimethylmorpholine;-   (S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(3-azaspiro[5.5]undecan-3-yl)phenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(4-(4-cyclohexylpiperidin-1-yl)-3,5-difluorophenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-4-(4-((2R,5R)-2,5-bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)pyrrolidin-1-yl)-2,6-difluorophenyl)-2-phenylmorpholine;-   (S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(4-phenylpiperazin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S,R)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((2S,4R)-4-fluoropyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(4-(4-(2,6-difluorophenyl)piperazin-1-yl)-3,5-difluorophenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(4-(4-(2,4-difluorophenyl)piperidin-1-yl)-3,5-difluorophenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(4-(4-fluorophenyl)piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2S,5S)-1-(4-(4-(2,6-difluorophenyl)piperazin-1-yl)-3,5-difluorophenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(4-(5-methylthiophen-2-yl)piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);    and-   (S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(4-fluoro-4-phenylpiperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole).

The following compounds as free base or salt can be made using GeneralProcedure 8, General Procedure 9B (Raney-nickel), General Procedure10/10A, and General Procedure 11/11A:

-   (S)-6,6′-((2R,5R)-1-(biphenyl-4-yl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(4-(cyclopentyloxy)-3-fluorophenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-((3aR,7aS)-1H-isoindol-2(3H,3aH,4H,5H,6H,7H,7aH)-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(3,5-dichloro-4-(piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(2,5-difluoro-4-(piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(4-((2R,6S)-2,6-dimethylpiperidin-1-yl)-3,5-difluorophenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(2,3,5-trifluoro-4-(piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(4-cyclohexyl-3-fluorophenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(3,4-difluorophenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(4-ethoxyphenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(4-(2,2-difluoroethoxy)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(4-(3,5-dimethylpiperidin-1-yl)-3,5-difluorophenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   6,6′-{(2R,5R)-1-[4-(pentafluoro-λ⁶-sulfanyl)phenyl]pyrrolidine-2,5-diyl}bis{2-[(2S)-pyrrolidin-2-yl]-1H-benzimidazole}    (ACD Name v12);-   (S)-6,6′-((2S,5S)-1-(4-cyclopropylphenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[c]imidazole);-   (S,S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((2S,4S)-4-methoxypyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S,S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(242S,4S)-4-fluoropyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S,S)-6,6′-((2R,5R)-1-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(2-((2S,4S)-4-fluoropyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S,S)-6,6′-((2R,5R)-1-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(2-((2S,4S)-4-methoxypyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(2-((S)-5,5-dimethylpyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S,S)-6,6′-((2R,5R)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(2-((2S,4S)-4-fluoropyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((3S)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-indolin-2-yl)-1H-benzo[d]imidazole);-   (S,R)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((2S,4R)-4-methoxypyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(2-((S)-4-methylenepyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(4-(4,4-diphenylpiperidin-1-yl)-3,5-difluorophenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   1-(1-(4-((2R,5R)-2,5-bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)pyrrolidin-1-yl)-2,6-difluorophenyl)-4-phenylpiperidin-4-yl)ethanone;-   (S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S,S,S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((2S,3aS,6aS)-octahydrocyclopenta[b]pyrrol-2-yl)-1H-benzo[d]imidazole);-   (S,S,S)-6,6′-((2R,5R)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(2-((2S,3aS,6aS)-octahydrocyclopenta[b]pyrrol-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(3-azaspiro[5.5]undecan-3-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(3-fluoro-4-(4-phenylpiperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S,S,S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(4-phenylpiperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((2S,3aS,6aS)-octahydrocyclopenta[b]pyrrol-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(3-phenylpiperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(3-phenylpyrrolidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(4-(pyrimidin-2-yl)piperazin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2S,5R)-1-(2-(4-phenylpiperidin-1-yl)pyrimidin-5-yl)pyrrolidine-2,5-diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);    and-   (S)-6,6′-((2S,5R)-1-(2-(piperidin-1-yl)pyrimidin-5-yl)pyrrolidine-2,5-diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole).

The following compounds as free base or salt can be made using GeneralProcedure 8, General Procedure 9E (Fe/NH₄Cl), General Procedure 10/10A,and General Procedure 11/11A:

-   (S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(4-(3-phenylpropyl)piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(6-azaspiro[2.5]octan-6-yl)phenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(4-(4-tert-butylpiperidin-1-yl)-3,5-difluorophenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(4-(naphthalen-2-yl)piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);    and-   (S)-6,6′-((2R,5R)-1-(4-(benzyloxy)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole).

Illustration of General Procedure 11. General Procedure 11C.(Monodeprotection)

(2S,3aS,6aS)-tert-butyl2-(5-((2R,5R)-1-(3,5-difluoro-4-(piperidin-1-yl)phenyl)-5-(2-((2S,3aS,6aS)-octahydrocyclopenta[b]pyrrol-2-yl)-1H-benzo[d]imidazol-5-yl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-2-yl)hexahydrocyclopenta[b]pyrrole-1(2H)-carboxylate

The starting di-Boc-protected amine (1.24 g, 1.36 mmol) was dissolved indichloromethane (12 mL) at ambient temperature and treated with aliquotsof trifluoroacetic acid (0.10 mL, 1.35 mmol) every thirty minutes for1.5 hours. The solution was concentrated to dryness then re-dissolvedinto dichloromethane and washed with sodium bicarbonate solution. Afterconcentration, the residue was purified by chromatography, eluting with0-20% methanol in dichloromethane to give 425 mg (38%) of the titlemono-deprotected amine as a yellow powder.

General Procedure 12. Endcap Addition.

Reaction of an amine with an acid to form an amide as depicted above canbe effected as described generally in Scheme 1 and other foregoingSchemes. The reaction can be promoted by a peptide coupling reagent,such as EDAC/HOBT, PyBOP, HATU, T3P or DEPBT, in a solvent such as THF,DMF, dichloromethane, ethyl acetate, or DMSO, with or without theaddition of an amine base such as Hunig's base, N-methylmorpholine,pyridine, 2,6-lutidine, or triethylamine, to give amide products. Forexample, an amine (1 equivalent) can be reacted with acids (2equivalents) such as, but not limited to,2-(methoxycarbonylamino)-3-methylbutanoic acid,2-(methoxycarbonylamino)-3,3-dimethylbutanoic acid,2-cyclohexyl-2-(methoxycarbonylamino)acetic acid,2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid, orthose listed below under General Procedure 19. Final coupling productsmay contain varying amounts of stereoisomers with respect to thepyrrolidine ring. In the case of fluoro-substitutedbenzimidazole-containing products (e.g. Example 6.1, Example 6.12,Example 6.16), final purification to remove residual amounts of anotherstereoisomer may require chiral chromatography as described below inGeneral Procedure 12C.

Illustration of General Procedure 12. General Procedure 12A

dimethyl(2S,2′S)-1,1′-((2S,2′S)-2,2′-(5,5′-((2R,5R)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(1H-benzo[d]imidazole-5,2-diyl)bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamateanddimethyl(2S,2′S)-1,1′-((2S,2′3)-2,2′-(5,5′-((2S,5S)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(1H-benzo[d]imidazole-5,2-diyl)bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate

(S)-5,5′-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole)(0.150 g, 0.261 mmol) and diisopropylethylamine (0.365 mL, 2.09 mmol)were dissolved in DMSO (3 mL) at room temperature and treated with(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (0.105 g, 0.601 mmol)followed by HATU (0.204 g, 0.536 mmol). The solution was stirred for 1hour at room temperature then diluted with water. The solid product wasfiltered off and purified by chromatography on silica gel with a 12 gcolumn, eluting with 0-8% methanol in dichloromethane to give 0.143 g(60%) of a yellow solid as a mixture of trans diastereomers. ¹H NMR (400MHz, DMSO-d₆) δ ppm 0.75-0.92 (m, 12H) 1.07 (s, 9H) 1.64-1.76 (m, 2H)1.85-2.04 (m, 6H) 2.12-2.26 (m, 4H) 2.43 (dd, J=7.75, 4.07 Hz, 2H) 3.53(s, 6H) 3.76-3.87 (m, 4H) 4.04 (dd, J=11.49, 6.51 Hz, 2H) 5.12 (t,J=7.59 Hz, 2H) 5.35 (d, J=3.25 Hz, 2H) 6.25 (d, J=8.46 Hz, 2H) 6.85-6.96(m, 2H) 7.07 (t, J=7.97 Hz, 2H) 7.19 (s, 1H) 7.28 (d, J=8.35 Hz, 3H)7.38 (dd, J=8.19, 1.90 Hz, 1H) 7.46 (d, J=8.13 Hz, 1H) 11.97-12.09 (m,2H).

Illustration of General Procedure 12. General Procedure 12B

dimethyl(2S,2′S)-1,1′-((2S,2′S)-2,2′-(4,4′-((2S,5S)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamateanddimethyl(2S,2′S)-1,1′-((2S,2′S)-2,2′-(4,4′-((2R,5R)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1-diyl)bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate

(2S,2′S)—N,N′—(4,4′-((2S,5S)-1-(4-tert-Butylphenyl)pyrrolidine-2,5-diyl)bis(4,1-phenylene))dipyrrolidine-2-carboxamideand(2S,2′S)—N,N′—(4,4′-((2R,5R)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(4,1-phenylene))dipyrrolidine-2-carboxamide(29.0 mg, 0.050 mmol), (S)-2-(methoxycarbonylamino)-3-methylbutanoicacid (19.27 mg, 0.110 mmol), EDAC (21.09 mg, 0.110 mmol), HOBT (16.85mg, 0.110 mmol) and N-methylmorpholine (0.027 mL, 0.250 mmol) werecombined in DMF (2 mL). The reaction mixture was stirred at roomtemperature for 3 hours. The mixture was partitioned between ethylacetate and water. The organic layer was washed with brine twice, driedwith sodium sulfate, filtered and evaporated. The residue was purifiedby chromatography on silica gel eluting with ethyl acetate in hexane(50% to 80%) to give a solid. The solid was triturated with ethylacetate/hexane to give the title compound (13 mg, 29%) as a mixture oftrans diastereomers. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.85-0.95 (m, 12H)1.11 (s, 9H) 1.59-1.65 (m, 2H) 1.79-2.04 (m, 8H) 2.10-2.18 (m, 2H)2.41-2.46 (m, 2H) 3.52 (s, 6H) 3.57-3.67 (m, 2H) 3.76-3.86 (m, 2H) 4.00(t, J=7.56 Hz, 2H) 4.39-4.46 (m, 2H) 5.15 (d, J=7.00 Hz, 2H) 6.17 (d,J=7.70 Hz, 2H) 6.94 (d, J=8.78 Hz, 2H) 7.13 (d, J=7.37 Hz, 4H) 7.30 (d,J=8.20 Hz, 2H) 7.50 (d, J=8.24 Hz, 4H) 9.98 (s, 2H); MS (ESI+) m/z 895(M+H)⁺.

Illustration of General Procedure 12. General Procedure 12C

methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-[3,5-difluoro-4-(piperidin-1-yl)phenyl]-5-{6-fluoro-2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-H-benzimidazol-5-yl}pyrrolidin-2-yl]-6-fluoro-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

To a solution of (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (116mg, 0.660 mmol) in CH₂Cl₂ (1.0 mL) was added EDC (127 mg, 0.660 mmol)and the solution was stirred at room temperature for 20 minutes. Thissolution was then cannulated into a solution of6,6′-{(2R,5R)-1-[3,5-difluoro-4-(piperidin-1-yl)phenyl]pyrrolidine-2,5-diyl}bis{5-fluoro-2-[(2S)-pyrrolidin-2-yl]-1H-benzimidazole}(ACD Name v12) (148 mg, 0.220 mmol) and Hunig's base (0.231 ml, 1.320mmol) in CH₂Cl₂ (1.000 mL) followed by the addition of HOBT (101 mg,0.660 mmol), and the solution was then stirred at room temperature for 1hour. The solution was diluted with CH₂Cl₂, washed with H₂O, dried(Na₂SO₄), filtered and concentrated. The product may be subject tofurther purification.

From a separate experiment using the above coupling procedure, crudeproduct (about 4 mmol) was purified on a Teledyne/ISCO Combiflash® RfSystem using a C18 cartridge eluting with 0-30% CH₃CN/(0.1% TFA/H₂O)over 30 minutes. The desired fractions were made basic with 10% NaHCO₃solution and extracted with EtOAc. The combined extracts were dried(Na₂SO₄), filtered and concentrated to give a white solid (545 mg). Thismaterial was then re-purified on a Waters preparative HPLC system usinga C18 column eluting with 0-95% CH₃CN/(0.1% TFA/H₂O) over 40 minutes togive material (195 mg) containing mostly the title compound and aresidual amount of a diastereomeric product. To remove remaining amountsof the diastereomer, chiral chromatography was run on this sample usinga Chiralpak® IA column (5 cm×15 cm, 20 mL/minute) and eluting with55/30/15 hexane/THF/[CH₃OH/EtOH 8:2] to give the title compound (116 mg,0.118 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 10.51-10.60 (m, 1H)10.33-10.41 (m, 1H) 7.43-7.50 (m, 1H) 7.32 (t, 1H) 7.13 (d, 1H) 6.93 (t,1H) 5.82 (d, 2H) 5.28-5.48 (m, 6H) 4.26-4.39 (m, 2H) 3.78-3.90 (m, 2H)3.70-3.71 (d, 6H) 3.57-3.67 (m, 2H) 3.44-3.57 (m, 1H) 2.99-3.12 (m, 2H)2.79-2.98 (m, 4H) 1.78-2.58 (m, 12H) 1.41-1.51 (m, 2H) 0.80-0.95 (m,12H); MS (ESI) m/z 987 (M+H)⁺.

General Procedure 14. Chiral Separation

dimethyl(2S,2′S)-1,1′-((2S,2′S)-2,2′-(5,5′-((2S,5S)-1-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(1H-benzo[d]imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate

The mixture of trans diastereomers was chromatographed by chiralchromatography on a Chiralpak IA column eluting with a mixture ofhexane/EtOH/CH₃OH/1,2-dichloroethane/diethylamine (25/25/25/25/0.1) togive two separate isomers. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.75-0.89 (m,12H) 1.64-1.73 (m, 2H) 1.85-2.03 (m, 6H) 2.12-2.24 (m, 4H) 2.81-2.90 (m,2H) 3.52 (s, 6H) 3.76-3.87 (m, 4H) 4.01-4.09 (m, 2H) 5.08-5.16 (m, 2H)5.34 (q, J=6.65 Hz, 2H) 6.26 (dd, J=9.05, 4.50 Hz, 2H) 6.67-6.78 (m, 2H)7.03 (t, J=8.02 Hz, 2H) 7.20 (s, 1H) 7.24-7.32 (m, 3H) 7.36 (d, J=8.13Hz, 1H) 7.44 (d, J=7.92 Hz, 1H) 12.01-12.07 (m, 2H). and

dimethyl(2S,2′S)-1,1′-((2S,2′S)-2,2′-(5,5′-((2R,5R)-1-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(1H-benzo[d]imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.74-0.93 (m, 12H) 1.69 (t, J=9.65 Hz,2H) 1.82-2.06 (m, 6H) 2.09-2.26 (m, 4H) 3.04-3.23 (m, 2H) 3.52 (s, 6H)3.73-3.90 (m, 4H) 4.06 (t, J=8.46 Hz, 2 H) 5.05-5.21 (m, 2H) 5.29-5.44(m, 2H) 6.21-6.32 (m, 2H) 6.67-6.86 (m, 2H) 7.05 (t, J=8.78 Hz, 2H) 7.18(s, 1H) 7.23-7.33 (m, 3H) 7.37 (d, J=8.13 Hz, 1H) 7.45 (d, J=8.02 Hz,1H) 12.04 (d, J=14.96 Hz, 2H).

General Procedure 15. Benzimidazole Synthesis Through MethoxybenzylamineDisplacement Route I

Shown generally in Scheme VIII, is a method of preparing certaincompounds (57) and (59). Illustrated below in General Procedure 15A is arepresentative synthesis of (57) where D is 4-tert-butylphenyl.

Illustration of General Procedure 15. General Procedure 15A

The five steps illustrated above are described by the followingexperimental procedures:

4,4′-(1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(N-(4-methoxybenzyl)-2-nitroaniline)

1-(4-tert-Butylphenyl)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidine (4.41g, 8.57 mmol) was combined, neat, with p-methoxy benzylamine (8.93 mL,68.6 mmol) and heated at 145° C. for 1 hour. The mixture was dilutedwith dichloromethane and filtered. The filtrate was washed with 0.5 MHCl, NaHCO₃ solution, and then brine. The organic phase was concentratedand purified by chromatography on silica gel with an 80 g column,eluting with 0-50% ethyl acetate/hexanes to give 4.13 g (67%) of anorange foamy solid.

4,4′-(1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(N1-(4-methoxybenzyl)benzene-1,2-diamine)

4,4′-(1-(4-tert-Butylphenyl)pyrrolidine-2,5-diyl)bis(N-(4-methoxybenzyl)-2-nitroaniline)(2 g, 2.79 mmol) was dissolved in a mixture of THF (15 mL), ethanol (15mL), and ethyl acetate (5 mL). Then platinum oxide (0.254 g, 1.12 mmol)was added as a THF slurry. The flask was evacuated and purged withnitrogen twice, then evacuated and opened to a hydrogen balloon. Themixture was stirred at room temperature for 20 hours, then filteredthrough diatomaceous earth, concentrated, and purified by chromatographyon silica gel with an 80 g column, eluting with 0-40% ethylacetate/dichloromethane to give the first peak of trans product (0.508g, 28%).

(2S,2′S)-tert-butyl2,2′-(5,5′-(1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(2-(4-methoxybenzylamino)-5,1-phenylene)bis(azanediyl)bis(oxomethylene))dipyrrolidine-1-carboxylate

4,4′-(1-(4-tert-Butylphenyl)pyrrolidine-2,5-diyl)bis(N1-(4-methoxybenzyl)benzene-1,2-diamine)(0.422 g, 0.643 mmol) and diisopropylethylamine (0.674 mL, 3.86 mmol)were dissolved in DMSO (6 mL) at room temperature and treated withS-Boc-proline (0.319 g, 1.48 mmol) followed by HATU (0.514 g, 1.35mmol). The solution was stirred for 1 hour at room temperature and thendiluted with water. The solid product was filtered off and purified bychromatography on silica gel with a 40 g column, eluting with 0-50%ethyl acetate in dichloromethane to give the title compound (0.565 g,84%) as a yellow solid.

(2S,2′S)-tert-butyl2,2′-(5,5′-(1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(2-amino-5,1-phenylene)bis(azanediyl)bis(oxomethylene))dipyrrolidine-1-carboxylate

(2S,2′S)-tert-Butyl2,2′-(5,5′-(1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(2-(4-methoxybenzylamino)-5,1-phenylene)bis(azanediyl)bis(oxomethylene))dipyrrolidine-1-carboxylate(0.565 g, 0.538 mmol) was dissolved in dichloromethane (5 mL) and water(0.25 mL) at room temperature and treated with DDQ (0.244 g, 1.076 mmol)portionwise over 2 minutes. The mixture was diluted with sodiumbicarbonate solution, extracted into dichloromethane, concentrated andpurified by chromatography on silica gel with a 40 g column, elutingwith 0-15% methanol/dichloromethane to give the title compound (0.355 g,81%) as a yellow solid.

(2S,2′S)-tert-butyl2,2′-(5,5′-(1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(1H-benzo[d]imidazole-5,2-diyl))dipyrrolidine-1-carboxylate

(2S,2′S)-tert-Butyl2,2′-(5,5′-(1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(2-amino-5,1-phenylene)bis(azanediyl)bis(oxomethylene))dipyrrolidine-1-carboxylatewas dissolved in neat acetic acid (3 mL) and heated at 72° C. for 2hours. The solution was concentrated and then poured into water. The pHwas adjusted to ˜7-8 with sodium bicarbonate. The product was extractedinto dichloromethane, concentrated and purified by chromatography onsilica gel with a 40 g column, eluting with 0-5%methanol/dichloromethane to give the title compound (0.185 g, 55%) as alight yellow solid.

General Procedure 16. Benzimidazole Synthesis Through MethoxybenzylamineDisplacement Route II

Shown generally in Scheme VIII, is a method of preparing certaincompounds (57) and (59). Illustrated below in General Procedure 16A is arepresentative synthesis of (57) where D is 4-fluorophenyl.

Illustration of General Procedure 16. General Procedure 16A

The five steps illustrated above are described by the followingexperimental procedures:

4,4′-(1-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(N-(4-methoxybenzyl)-2-nitroaniline)

2,5-Bis(4-chloro-3-nitrophenyl)-1-(4-fluorophenyl)pyrrolidine (0.88 g,1.86 mmol) was combined with 4-methoxy benzylamine (3.64 mL, 28.0 mmol)and heated at 145° C. for 1 hour in a microwave reactor. The mixture wasdiluted with dichloromethane and filtered. The filtrate was concentratedand purified by chromatography on silica gel with a 330 g column,eluting with 0-60% ethyl acetate/hexanes to give 0.79 g (62%) of anorange foam solid.

4,4′-(1-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(2-nitroaniline)

4,4′-(1-(4-Fluorophenyl)pyrrolidine-2,5-diyl)bis(N-(4-methoxybenzyl)-2-nitroaniline)(0.78 g, 1.15 mmol) was dissolved in dichloromethane (10 mL) at roomtemperature and treated with TFA (1.8 mL, 23.0 mmol) for 3 hours. Theresidue was concentrated and partitioned between dichloromethane andsodium bicarbonate solution. The organics were concentrated and purifiedby chromatography on silica gel with a 40 g column, eluting withdichloromethane to give 0.218 g (43%) of the trans isomer.

4,4′-(1-(4-fluorophenyl)pyrrolidine-2,5-diyl)dibenzene-1,2-diamine

4,4′-(1-(4-Fluorophenyl)pyrrolidine-2,5-diyl)bis(2-nitroaniline) (0.218g, 0.50 mmol) was dissolved in DMF (5 mL) then platinum oxide (0.226 g,0.99 mmol) was added as a THF slurry. The flask was evacuated and purgedwith nitrogen twice, then evacuated and opened to hydrogen balloon. Themixture was stirred at room temperature for 20 hours. The solution wastaken on to the next step without purification.

(2S,2′S)-tert-butyl2,2′-(5,5′-(1-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(2-amino-5,1-phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-1-carboxylate

The crude DMF solution of4,4′-(1-(4-fluorophenyl)pyrrolidine-2,5-diyl)dibenzene-1,2-diamine wastreated with diisopropylethylamine (0.296 mL, 1.70 mmol) andS-Boc-proline (0.192 g, 0.89 mmol) followed by HATU (0.322 g, 0.85mmol). The solution was stirred for 1.5 hours at room temperature, andthen the reaction mixture was diluted with water. The solid product wasfiltered off and purified by chromatography on silica gel with a 12 gcolumn, eluting with 0-3% methanol in dichloromethane to give 0.235 g(72%) of a yellow solid, for which the regiochemistry of acylation wasarbitrarily assigned as reacting at the meta-amino group.

(2S,2′S)-tert-butyl2,2′-(5,5′-(1-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(1H-benzo[d]imidazole-5,2-diyl))dipyrrolidine-1-carboxylate

(2S,2′S)-tert-Butyl2,2′-(5,5′-(1-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(2-amino-5,1-phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-1-carboxylatewas dissolved in neat acetic acid (2 mL) and heated at 60° C. for 1hour. The solution was concentrated then poured into water and adjustedpH to ˜7-8 with sodium bicarbonate. The product was extracted intodichloromethane, concentrated and purified by chromatography on silicagel with a 12 g column, eluting with 0-20% ethyl acetate indichloromethane to give the title compound (0.124 g, 55%) as a lightyellow solid.

General Procedure 17. Suzuki Couplings Off N-Aryl Group

Intermediate compounds such as2,5-bis(4-chloro-3-nitrophenyl)-1-(4-iodophenyl)pyrrolidine (or thecorresponding triflate, nonaflate, or bromide) can be further elaboratedthrough a Suzuki reaction as shown with an appropriate boronic acid orester where R_(Suz) represents a suitable cycloalkyl, aryl,cycloalkenyl, or heteroaryl group. Suitable conditions for effectingthis Suzuki reaction include those described in Scheme V for thesynthesis of compounds (37).

Illustration of General Procedure 17: General Procedure 17A

4-(5-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)phenyl)pyridin-2-yl)morpholine

(2R,5R)-2,5-Bis(4-chloro-3-nitrophenyl)-1-(4-iodophenyl)pyrrolidine(1.869 g, 3.2 mmol),4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine(0.929 g, 3.20 mmol), potassium phosphate (1.359 g, 6.40 mmol),tris(dibenzylideneacetone)dipalladium(0) (0.029 g, 0.032 mmol) and1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamante (0.028 g,0.096 mmol) were combined in THF (18 mL)/water (6 mL). The mixture waspurged with nitrogen for 15 minutes and stirred at room temperature for24 hours. The reaction mixture was partitioned between ethyl acetate andsaturated sodium bicarbonate. The organic layer was washed with brine,dried with sodium sulfate, filtered and evaporated. The residue waspurified by chromatography on silica gel eluting with ethylacetate/hexane (20% to 40%) to give the title compound (1.01 g, 51%) asa solid.

General Procedure 18. Proline Amide Synthesis

Particular substituted proline amides can be made using methods such asthose shown in General Procedures 18A-18C.

Illustration of General Procedure 18. General Procedure 18A

methyl(2S)-1-((3S)-3-carbamoyl-2-azabicyclo[2.2.1]heptan-2-yl)-3-methyl-1-oxobutan-2-ylcarbamate

(3S)-2-((S)-2-(Methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[2.2.1]heptane-3-carboxylicacid (1.78 g, 5.97 mmol),2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate (2.49 g, 5.56 mmol), and diisopropylethylamine (2.61mL, 14.92 mmol) were dissolved in acetonitrile (30 mL) at ambienttemperature and treated by dropwise addition with 28% ammonium hydroxidesolution (2.49 g, 17.98 mmol). The resulting mixture was stirred for 1hour and then diluted with water and extracted into dichloromethane. Theorganic layer was washed with brine, dried over sodium sulfate,filtered, and concentrated to give methyl(2S)-1-((3S)-3-carbamoyl-2-azabicyclo[2.2.1]heptan-2-yl)-3-methyl-1-oxobutan-2-ylcarbamateas a white waxy solid.

Illustration of General Procedure 18. General Procedure 18B

(2S,4S)-tert-butyl 2-carbamoyl-4-methoxypyrrolidine-1-carboxylate

(2S,4S)-1-(tert-Butoxycarbonyl)-4-methoxypyrrolidine-2-carboxylic acid(2.9 g, 11.82 mmol) was dissolved in acetonitrile (150 mL) and cooled inan ice bath.N¹—((Ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochloride (2.72 g, 14.19 mmol) and 1H-benzo[d][1,2,3]triazol-1-olhydrate (2.17 g, 14.19 mmol) were added, and the mixture was stirred atambient temperature for 15 hours, becoming clear. 28% Ammonium hydroxide(4.93 mL, 35.5 mmol) was added dropwise resulting in a precipitate.After stirring for 2 hours, then mixture was concentrated, diluted withwater and extracted into ethyl acetate. The organic layer was washedwith brine, dried over sodium sulfate, filtered, and concentrated togive 100% yield of (2S,4S)-tert-butyl2-carbamoyl-4-methoxypyrrolidine-1-carboxylate as a white waxy solid.

Other amides that can be prepared using General Procedure 18B include:

-   (2S,4R)-tert-butyl 2-carbamoyl-4-methoxypyrrolidine-1-carboxylate;-   (2S,4S)-tert-butyl 2-carbamoyl-4-fluoropyrrolidine-1-carboxylate;    and-   (S)-tert-butyl 5-carbamoyl-2,2-dimethylpyrrolidine-1-carboxylate.

Illustration of General Procedure 18. General Procedure 18C

(S)-tert-butyl 2-carbamoyl-4-methylenepyrrolidine-1-carboxylate

(5)-1-(tert-Butoxycarbonyl)-4-methylenepyrrolidine-2-carboxylic acid(1.05 g, 4.48 mmol) and N-methylmorpholine (0.64 mL, 5.83 mmol) weredissolved in tetrahydrofuran (25 mL) and cooled to −15° C. in a dryice/acetone bath. Isobutyl chloroformate (0.65 mL, 4.93 mmol) was addeddropwise and the solution was stirred for 15 minutes. The internaltemperature was lowered to −25° C. and ammonia (g) was bubbled throughthe solution for 2 minutes, then the flask was transferred to an icebath and stirred for another 20 minutes. The solution was poured intobrine and extracted into ethyl acetate, dried over magnesium sulfate,filtered and concentrated. This residue was triturated withether/hexanes, filtered, and dried to give 0.97 g (81%) of(S)-tert-butyl 2-carbamoyl-4-methylenepyrrolidine-1-carboxylate as awhite solid.

General Procedure 19

Amino acid carbamate intermediates can be made using the method andgeneral illustration shown above to prepare Intermediate 2.

The following compounds can be made following General Procedure 19starting from the appropriate amino acid:

-   (S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic    acid;-   (S)-2-cyclohexyl-2-(methoxycarbonylamino)acetic acid;-   (S)-2-cyclopentyl-2-(methoxycarbonylamino)acetic acid;-   (S)-2-cyclobutyl-2-(methoxycarbonylamino)acetic acid;-   (S)-2-cyclopropyl-2-(methoxycarbonylamino)acetic acid;-   (S)-2-(methoxycarbonylamino)-3,3-dimethylbutanoic acid;-   (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid;-   (2S,3S)-3-methoxy-2-(methoxycarbonylamino)butanoic acid;-   (S)-2-(methoxycarbonylamino)-2-((R)-tetrahydrofuran-3-yl)acetic    acid;-   (S)-2-(methoxycarbonylamino)-2-((S)-tetrahydrofuran-3-yl)acetic    acid;-   (S)-2-(2,3-dihydro-1H-inden-2-yl)-2-(methoxycarbonylamino)acetic    acid.-   (S)-3-ethyl-2-(methoxycarbonylamino)pentanoic acid; and-   (S)-2-(ethoxycarbonylamino)-3-methylbutanoic acid.

General Procedure 20

As described above generally in Scheme XIII, diamines (79) can beconverted to benzimidazoles (81) in two steps.

Illustration of General Procedure 20. General Procedure 20A(S)-tert-butyl2-(6-bromo-5-fluoro-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate

To a solution of 4-bromo-5-fluorobenzene-1,2-diamine (1.7 g, 8.4 mmol)in DMSO (42 mL) was added(S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (1.8 g, 8.4mmol) followed by HATU (3.5 g, 9.3 mmol) andN,N-diisopropyl-N-ethylamine (3.7 mL, 21.1 mmol), and the solution wasstirred for 16 hours. The reaction mixture was diluted with EtOAc,washed with H₂O and brine, dried (Na₂SO₄), filtered and concentrated.Acetic acid (40 mL) was added, and the mixture was stirred at 60° C. for4 hours. Then, the reaction mixture was cooled and concentrated. Theresidue was azeotroped 2 times with toluene to give crude product whichwas purified by flash chromatography (0-50% EtOAc/hexane) to give thetitle compound (2.5 g, 6.4 mmol, 77%).

(S)-tert-butyl2-(5-bromo-6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate

To a solution of (S)-tert-butyl2-(6-bromo-5-fluoro-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate(2.5 g, 6.4 mmol) in THF (32 mL) was added sodium hydride (0.27 g, 6.8mmol) and stirring was continued for 30 minutes.2-(Trimethylsilyl)-ethoxymethyl chloride (1.2 mL, 6.8 mmol) was addedand stirring was continued for 30 minutes. Water was added to quench thereaction. The mixture was diluted with EtOAc, washed with 1N HCl, H₂O,and brine, dried (Na₂SO₄), filtered and concentrated to an oil. The oilwas purified by flash chromatography (0-30% EtOAc/hexane) to give thetitle compound (2.9 g, 5.7 mmol, 89%).

The following compounds of general formula (81) can be made followingGeneral Procedure 20 starting from the appropriate diamine:

-   (S)-tert-butyl 2-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methy    1)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate;-   (S)-tert-butyl    2-(5-bromo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate;-   (S)-tert-butyl    2-(5-bromo-4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[c]imidazol-2-yl)pyrrolidine-1-carboxylate;-   (S)-tert-butyl    2-(5-bromo-4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate;-   (S)-tert-butyl    2-(6-bromo-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-2-yl)pyrrolidine-1-carboxylate;-   (S)-tert-butyl    2-(5-bromo-7-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate;-   (S)-tert-butyl    2-(5-bromo-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate;-   (S)-tert-butyl    2-(5-bromo-6-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methy    1)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate;-   (S)-tert-butyl    2-(5-bromo-7-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate;-   (S)-tert-butyl    2-(5-bromo-6-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate;-   (S)-tert-butyl    2-(5-bromo-7-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate;    and-   (S)-methyl    5-bromo-2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[c]imidazole-7-carboxylate.

General Procedure 21

As described above generally in Scheme XIII, compounds (81) can beconverted to compounds (82.2). Illustrated below in General Procedure21A is a representative synthesis of compounds (82.2) where X₁₃ isfluoro at the 6-position of the benzimidazole moiety. For convenientillustration, the SEM protecting groups on the benzimidazoles are shownattached to particular nitrogens of the benzimidazole. In GeneralProcedures 21A and 22A, the actual substitution positions of the SEMgroups were not determined and may be at either nitrogen.

Illustration of General Procedure 21. General Procedure 21A.

(2S,2′S)-tert-butyl2,2′-(5,5′-(furan-2,5-diyl)bis(6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5,2-diyl))dipyrrolidine-1-carboxylate

In a pressure tube were combined (S)-tert-butyl2-(5-bromo-6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate(600 mg, 1.2 mmol),2,5-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)furan (186 mg, 0.6mmol), cesium fluoride (353 mg, 2.3 mmol) and DMF (4 mL), and themixture was de-gassed with N₂ gas for 30 minutes. To this mixture wasadded [(t-Bu)₂PCl]₂PdCl₂ (PXPd) (15.7 mg, 0.03 mmol) and the tube wassealed and heated at 100° C. for 18 hours. The cooled solution wasdiluted with EtOAc, filtered through diatomaceous earth. The filtratewas washed with H₂O and brine, dried (Na₂SO₄), filtered and treated with3-mercaptopropyl silica gel for 30 minutes. The mixture was filtered,and the filtrate concentrated to give crude product which was purifiedby flash chromatography (0-50% EtOAc/hexane) to give the title compound(269 mg, 0.29 mmol, 50%).

di-tert-butyl(2S,2′S)-2,2′-{[(2E)-1,4-dioxobut-2-ene-1,4-diyl]bis(6-fluoro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-5,2-diyl)}dipyrrolidine-1-carboxylate(ACD Name v12)

To a solution of (2S,2′S)-tert-butyl2,2′-(5,5′-(furan-2,5-diyl)bis(6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5,2-diyl)dipyrrolidine-1-carboxylate(340 mg, 0.36 mmol) in THF (8 mL) was added Selectfluor®(1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate)) (258 mg, 0.73 mmol) followed by H₂O (1 mL). Thesolution was stirred for 1 hour, diluted with EtOAc, washed with H₂O andbrine, dried (Na₂SO₄), filtered and concentrated to give the titlecompound.

di-tert-butyl(2S,2′S)-2,2′-[(1,4-dioxobutane-1,4-diyl)bis(6-fluoro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-5,2-diyl)]dipyrrolidine-1-carboxylate(ACD Name v12)

To a solution of di-tert-butyl(2S,2′S)-2,2′-{[(2E)-1,4-dioxobut-2-ene-1,4-diyl]bis(6-fluoro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-5,2-diyl)}dipyrrolidine-1-carboxylate(346 mg, 0.36 mmol) in EtOAc (7 mL) was added platinum (3% on carbon)(71 mg, 0.36 mmol) and the solution was stirred under H₂ gas at 1 atmfor 2 hours. The solution was filtered, washed with EtOAc and thefiltrate concentrated to give a residue which was purified by flashchromatography (0-50% EtOAc/hexane) to give the title compound (269 mg,0.28 mmol, 78%).

General Procedure 22

As described above generally in Scheme XIII, compounds (82.2) can beconverted to compounds (84). Illustrated below in General Procedure 22Ais a representative synthesis of compounds (84) where D is4-tert-butylphenyl, the stereochemistries of the alcohols on thebutane-1,4-diyl group are both (5), and X₁₃ is 6-fluoro. The cyclizationto form the pyrrolidine can form the trans-pyrrolidine along withvarying amounts of the cis-pyrrolidine. The cis-pyrrolidine may beseparated after deprotection (see General Procedure 23) or after anystep following the deprotection.

Illustration of General Procedure 22. General Procedure 22A

di-tert-butyl(2S,2′S)-2,2′-{[(1S,4S)-1,4-dihydroxybutane-1,4-diyl]bis(6-fluoro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-5,2-diyl)}dipyrrolidine-1-carboxylate(ACD Name v12)

To a solution of (R)-(+)-α,α-diphenyl-2-pyrrolidinemethanol (59.9 mg,0.24 mmol) in THF (2.8 mL) was added trimethylborate (0.034 mL, 0.31mmol), and the resultant solution was stirred for 90 minutes. Thesolution was cooled to 0° C. and N,N-diethylaniline borane (0.4 mL, 2.2mmol) was added in portions over 30 minutes with stirring continued at0° C. This solution was added via cannula to a 0° C. solution ofdi-tert-butyl(2S,2′S)-2,2′-[(1,4-dioxobutane-1,4-diyl)bis(6-fluoro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-5,2-diyl)]dipyrrolidine-1-carboxylate(265 mg, 0.28 mmol) in THF (2.8 mL) and then warmed to room temperatureand stirred for 16 hours. The solution was cooled to 0° C. and CH₃OH(0.09 mL, 2.2 mmol) was added, and the solution was warmed to roomtemperature and stirred for 2 hours. 1N HCl was added, and the aqueoussolution was extracted with EtOAc. The combined extracts were washedwith brine, dried (Na₂SO₄), filtered and concentrated. Purification wasrun by flash chromatography (0-3% CH₃OH/CH₂Cl₂) to give the titlecompound (248 mg, 0.26 mmol, 93%).

di-tert-butyl(2S,2′S)-2,2′-{[(2R,5R)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis(6-fluoro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-5,2-diyl)}dipyrrolidine-1-carboxylate(ACD Name v12)

To a solution of di-tert-butyl(2S,2′S)-2,2′-{[(1S,4S)-1,4-dihydroxybutane-1,4-diyl]bis(6-fluoro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-5,2-diyl)}dipyrrolidine-1-carboxylate(100 mg, 0.10 mmol) in CH₂Cl₂ (1 mL) at −20° C. was added triethylamine(0.044 mL, 0.31 mmol) followed by mesyl chloride (0.018 mL, 0.23 mmol)and the solution stirred at −20° C. for 1 hour. 4-tert-Butyl aniline(0.083 mL, 0.52 mmol) was added in one portion, and the solution wasallowed to warm to room temperature overnight, with stirring. Thesolution was diluted with EtOAc, washed with 1N HCl, H₂O, and brine,dried (Na₂SO₄), filtered and concentrated. Purification by flashchromatography (0-50% EtOAc/hexane) gave the title compound (46 mg, 0.04mmol, 41%).

General Procedure 23. De-boc/de-SEM Procedure

Simultaneous removal of Boc and SEM protecting groups, according to theabove depiction can be effected using standard conditions such as bytreatment with an acid, such as HCl in solvents such as dioxane ormethanol or mixtures thereof at temperature from about room temperatureto about 60° C. The compounds obtained on deprotection may consist of amixture of stereoisomers that may be separated by reverse-phase HPLC.The de-protected compounds obtained may be isolated as either the saltdirectly from the reaction or reverse-phase HPLC or as the free basefollowing neutralization, extraction into organic solvent and standardisolation.

Illustration of General Procedure 23. General Procedure 23A

6,6′-[(2R,5R)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis{5-fluoro-2-[(2S)-pyrrolidin-2-yl]-1H-benzimidazole}(ACD Name v12)

To a solution of di-tert-butyl(2S,2′R)-2,2′-{[(2R,5R)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis(6-fluoro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-5,2-diyl)}dipyrrolidine-1-carboxylate(44 mg, 0.04 mmol) in dioxane (1 mL) was added 4 M HCl/dioxane (1 mL,4.0 mmol) and the solution was stirred at 50° C. for 2 hours. The cooledsolution was concentrated and placed under vacuum for 1 hour to providethe crude title compound that was used without purification.

The following list of diamines

-   4-bromo-3-methylbenzene-1,2-diamine;-   5-bromo-3-fluorobenzene-1,2-diamine;-   4-bromo-3-fluorobenzene-1,2-diamine;-   4-bromo-3-chlorobenzene-1,2-diamine; and-   4-bromo-5-fluorobenzene-1,2-diamine.    can be subjected to a sequence of General Procedures 20/20A, 21/21A,    22/22A, 23/23A to give the following compounds:-   6,6′-[1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis{4-fluoro-2-[(2S)-pyrrolidin-2-yl]-1H-benzimidazole}    (ACD Name v12);-   6,6′-[(2R,5R)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis{7-fluoro-2-[(2S)-pyrrolidin-2-yl]-1H-benzimidazole}    (ACD Name v12);-   6,6′-[(2R,5S)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis{7-fluoro-2-[(2S)-pyrrolidin-2-yl]-1H-benzimidazole}    (ACD Name v12);-   6,6′-[(2R,5R)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis{7-chloro-2-[(2S)-pyrrolidin-2-yl]-1H-benzimidazole}    (ACD Name v12);-   6,6′-[(2R,5S)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis{7-chloro-2-[(2S)-pyrrolidin-2-yl]-1H-benzimidazole}    (ACD Name v12);-   6,6′-[(2R,5R)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis{7-methyl-2-[(2S)-pyrrolidin-2-yl]-1H-benzimidazole}    (ACD Name v12);-   6,6′-[(2R,5S)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis{7-methyl-2-[(2S)-pyrrolidin-2-yl]-1H-benzimidazole}    (ACD Name v12);-   6,6′-{(2R,5R)-1-[3-fluoro-4-(piperidin-1-yl)phenyl]pyrrolidine-2,5-diyl}bis{5-fluoro-2-[(2S)-pyrrolidin-2-yl]-1H-benzimidazole}    (ACD Name v12);-   6,6′-{(2R,5R)-1-[3,5-difluoro-4-(piperidin-1-yl)phenyl]pyrrolidine-2,5-diyl}bis{5-fluoro-2-[(2S)-pyrrolidin-2-yl]-1H-benzimidazole}    (ACD Name v12); and-   6,6′-{(2R,5R)-1-[3,5-difluoro-4-(4-phenylpiperidin-1-yl)phenyl]pyrrolidine-2,5-diyl}bis{5-fluoro-2-[(2S)-pyrrolidin-2-yl]-1H-benzimidazole}    (ACD Name v12).

EXAMPLES

The following example compounds 1.1-1.8 can be made from the appropriatelisted substituted pyrrolidine following the methods of GeneralProcedure 8.1, General Procedure 9C (Raney-nickel), and GeneralProcedure 10B.

Pyrrolidines:

-   (2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)-1-(4-phenoxyphenyl)pyrrolidine;-   1-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)phenyl)pyridin-2(1H)-one;-   (2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)-1-(2,5-difluoro-4-(trifluoromethyl)phenyl)pyrrolidine;-   4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2-fluoropyridine;-   1-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-4,4-difluoropiperidine;-   1-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-4-fluoropiperidine;-   (2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)-1-(4-((3-ethyloxetan-3-yl)methoxy)phenyl)pyrrolidine;    and-   (1R,5S)-3-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-3-azabicyclo[3.2.0]heptane.

Example 1.1methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}-1-(4-phenoxyphenyl)pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.78-0.91 (m, 12H) 1.70 (d, J=6.83 Hz,2H) 1.86-1.96 (m, 2H) 1.99 (d, J=2.17 Hz, 4H) 2.15-2.25 (m, 4H)2.55-2.61 (m, 2H) 3.54 (s, 6H) 3.82 (s, 4H) 4.06 (t, J=8.40 Hz, 2H) 5.13(t, J=7.26 Hz, 2H) 5.35-5.43 (m, 2H) 6.35 (d, J=9.11 Hz, 2H) 6.62-6.69(m, 2H) 6.71 (d, J=8.02 Hz, 2H) 6.93 (t, J=7.43 Hz, 1H) 7.08 (t, J=9.43Hz, 2H) 7.18-7.25 (m, 3H) 7.27-7.34 (m, 3H) 7.39 (d, J=8.13 Hz, 1H) 7.47(d, J=8.02 Hz, 1H) 12.05 (d, J=12.04 Hz, 2H); MS (ESI+) m/z 924.4(M+H)⁺.

Example 1.2methyl{(2S)-1-[(2S)-2-(5-{(2R,5R)-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}-1-[4-(2-oxopiperidin-1-yl)phenyl]pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.76-0.92 (m, 12H) 1.66-1.76 (m, 6H)1.91 (dd, J=13.61, 7.54 Hz, 2H) 1.95-2.04 (m, 4H) 2.20 (dd, J=16.26,3.80 Hz, 6H) 2.58-2.64 (m, 2H) 3.39-3.45 (m, 2H) 3.54 (s, 6H) 3.82 (s,4H) 4.02-4.09 (m, 2H) 5.09-5.19 (m, 2H) 5.35-5.43 (m, 2H) 6.29 (d,J=8.89 Hz, 2H) 6.70-6.78 (m, 2H) 7.07 (d, J=8.13 Hz, 2H) 7.22 (s, 1H)7.29 (d, J=8.35 Hz, 2 H) 7.33 (s, 1H) 7.38 (d, J=8.35 Hz, 1H) 7.47 (d,J=8.13 Hz, 1H) 12.04 (s, 2H); MS (ESI+) m/z 929.5 (M+H)⁺.

Example 1.3methyl{(2S)-1-[(2S)-2-{5-[(2S,5R)-1-[2,5-difluoro-4-(trifluoromethyl)phenyl]-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.76-0.94 (m, 12H) 1.83-2.07 (m, 8H)2.14-2.28 (m, 4H) 2.35-2.45 (m, 2H) 3.54 (s, 6H) 3.75-3.94 (m, 4H) 4.07(dd, J=8.19, 4.93 Hz, 2H) 5.19 (dd, J=31.50, 3.74 Hz, 44-1) 6.48-6.61(m, 1H) 7.20-7.35 (m, 5H) 7.40-7.46 (m, 1H) 7.49-7.56 (m, 2 H) 7.58-7.65(m, 1H) 12.12 (d, J=4.66 Hz, 2H); MS (APCI+) m/z 936.24 (M+H)⁺.

Example 1.4methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-(2-fluoropyridin-4-yl)-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.77-0.91 (m, 12H) 1.32 (td, J=14.99,7.43 Hz, 1H) 1.53 (dt, J=21.23, 6.63 Hz, 1H) 1.74 (dd, J=11.93, 6.07 Hz,2H) 1.86-2.05 (m, 6H) 2.14-2.23 (m, 4H) 3.54 (s, 6H) 3.77-3.86 (m, 4H)4.05-4.10 (m, 2H) 5.11-5.18 (m, 2H) 5.45-5.59 (m, 2H) 5.79 (s, 1 H)6.18-6.23 (m, 1H) 7.03-7.13 (m, 2H) 7.23 (s, 1H) 7.29 (d, J=8.35 Hz, 2H)7.34 (d, J=1.52 Hz, 1H) 7.42 (d, J=8.35 Hz, 1H) 7.47-7.56 (m, 2H) 12.11(s, 2H); MS (ESI+) m/z 851.3 (M+H)⁺.

Example 1.5methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-[4-(4,4-difluoropiperidin-1-yl)-3,5-difluorophenyl]-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.74-0.93 (m, 12H) 1.63-1.74 (m, 2H)1.85-2.06 (m, 12 H) 2.19 (dd, J=9.49, 5.37 Hz, 4H) 2.86-2.96 (m, 4H)3.54 (s, 6H) 3.76-3.86 (m, 4H) 4.07 (t, J=8.24 Hz, 2H) 5.09-5.20 (m, 2H)5.33-5.42 (m, 2H) 5.92 (d, J=12.90 Hz, 2H) 7.07 (t, J=7.37 Hz, 2H) 7.21(s, 1H) 7.26-7.33 (m, 3H) 7.41 (d, J=8.13 Hz, 1H) 7.49 (d, J=8.13 Hz,1H) 12.08 (d, J=12.90 Hz, 2H); MS (ESI+) m/z 987.5 (M+H)⁺.

Example 1.6methyl{1-[(2S)-2-{5-[(2R,5R)-1-[3,5-difluoro-4-(4-fluoropiperidin-1-yl)phenyl]-5-{2-[(2S)-1-{2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.74-0.91 (m, 12H) 1.63-1.71 (m, 6H)1.76-1.97 (m, 4H) 1.98-2.07 (m, 4H) 2.14-2.23 (m, 4H) 2.71-2.78 (m, 2H)2.90-3.00 (m, 2H) 3.54 (s, 6H) 3.82 (s, 4H) 4.06 (t, J=8.73 Hz, 2H)4.58-4.78 (m, 1H) 5.11-5.18 (m, 2H) 5.33-5.43 (m, 2H) 5.90 (d, J=12.69Hz, 2H) 7.07 (t, J=7.37 Hz, 2H) 7.20 (s, 1H) 7.26-7.32 (m, 3H) 7.41 (d,J=8.24 Hz, 1H) 7.49 (d, J=8.24 Hz, 1H) 12.07 (d, J=16.48 Hz, 2H); MS(ESI+) m/z 969.5 (M+H)⁺.

Example 1.7methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-{4-[(3-ethyloxetan-3-yl)methoxy]phenyl}-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ 12.26-11.98 (m, 2H), 7.44 (d, J=8.2, 1H),7.37 (d, J=8.2, 1H), 7.33-7.18 (m, 4H), 7.05 (t, J=8.1, 2H), 6.62-6.53(m, 2H), 6.26 (d, J=8.8, 2H), 5.40-5.30 (m, 2H), 5.17-5.08 (m, 2H), 4.29(d, J=5.7, 2H), 4.22 (d, J=5.8, 2H), 4.06 (t, J=8.3, 2H), 3.86-3.75 (m,6H), 3.53 (s, 6H), 2.54 (s, 2H), 2.24-2.12 (m, 4H), 2.06-1.83 (m, 6H),1.75-1.62 (m, 4H), 0.91-0.74 (m, 15H); MS (ESI+) m/z 946.5 (M+H)⁺.

Example 1.8methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-{4-[(1R,5S)-3-azabicyclo[3.2.0]hept-3-yl]-3,5-difluorophenyl}-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.82 (s, 12H) 1.61 (s, 3H) 1.71 (d, 2H)1.97 (m, 9H) 2.20 (s, 2H) 2.74-2.78 (m, 2H) 2.85 (s, 5H) 3.53 (s, 6H)3.82 (s, 3H) 4.06 (s, 2H) 5.14 (s, 2H) 5.38 (s, 2 H) 5.91 (s, 2H) 7.09(s, 1H) 7.37 (m, 6H) 7.63 (s, 1H) 7.88 (s, 1H) 12.05 (s, 2H); MS (ESI+)m/z 963.5 (M+H)⁺, (ESI−) m/z 961.4 (M−H)⁻.

The following example compounds 2.1-2.17 can be made from theappropriate listed substituted pyrrolidine following the methods ofGeneral Procedure 8.1, General Procedure 9D (PtO2), and GeneralProcedure 10B.

Pyrrolidines:

-   2-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)phenyl)oxazole;-   (2R,5R)-1-(4-chloro-3-fluorophenyl)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidine;-   (2R,5R)-1-(4-(1,3-dioxan-5-yloxy)phenyl)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidine;-   (2R,5R)-1-(4-((1,3-dioxolan-4-yl)methoxy)phenyl)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidine;-   (2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)-1-(4-((3-ethyloxetan-3-yl)methoxy)-3,5-difluorophenyl)pyrrolidine;-   1-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,3,5,6-tetrafluorophenyl)piperidine;-   (2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)-1-(3-fluoro-4-(methylsulfonyl)phenyl)pyrrolidine    (obtained by mCPBA oxidation of    (2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)-1-(3-fluoro-4-(methylthio)phenyl)pyrrolidine);-   4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-N-tert-butyl-2-fluoroaniline;-   1-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-4-methylpiperidine;-   1-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-4-(3-phenylpropyl)piperidine;-   8-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-8-azaspiro[4.5]decane;-   1-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-4-(naphthalen-2-yl)piperidine;-   2-(1-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)piperidin-4-yl)pyridine;-   1-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-4-(4-(trimethylsilyl)phenyl)piperidine;-   1-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-4-(naphthalen-1-yl)piperidine;-   1-(4-((2R,5R)-2,5-bis(4-chloro-2-fluoro-5-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-3,5-dimethylpiperidine;    and-   1-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-4-(4-(trifluoromethyl)phenyl)piperazine.

Example 2.1methyl{(2S)-1-[(2S)-2-(5-{(2R,5R)-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}-1-[4-(1,3-oxazol-2-yl)phenyl]pyrrolidin-2-yl}-1H-benzimidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.74-0.91 (m, 12H) 1.70-1.79 (m, 2H)1.89 (ddd, J=14.20, 7.05, 6.94 Hz, 2H) 1.95-2.04 (m, 4H) 2.13-2.23 (m,4H) 2.55-2.61 (m, 2H) 3.53 (s, 6H) 3.77-3.84 (m, 4H) 4.05 (t, J=8.67 Hz,2H) 5.09-5.18 (m, 2H) 5.46-5.54 (m, 2H) 6.45 (d, J=8.89 Hz, 2 H) 7.08(t, J=7.75 Hz, 2H) 7.13 (s, 1H) 7.23 (s, 1H) 7.28 (d, J=8.24 Hz, 2H)7.33 (s, 1H) 7.39 (d, J=8.13 Hz, 1H) 7.45-7.56 (m, 3H) 7.94 (s, 1H)12.06 (s, 2H); MS (EST+) m/z 899.4 (M+H)⁺.

Example 2.2methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-(4-chloro-3-fluorophenyl)-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.77-0.90 (m, 12H) 1.66-1.78 (m, 2H)1.88-1.95 (m, 2H) 1.96-2.06 (m, 4H) 2.15-2.24 (m, 4H) 2.54-2.60 (m, 2H)3.54 (s, 6H) 3.79-3.86 (m, 4H) 4.06 (t, J=8.46 Hz, 2H) 5.10-5.18 (m, 2H)5.37-5.45 (m, 2H) 6.16 (dd, J=9.49, 2.01 Hz, 1H) 6.22 (dd, J=13.55, 2.06Hz, 1H) 7.00-7.11 (m, 3H) 7.22 (s, 1H) 7.28 (d, J=8.57 Hz, 2H) 7.32 (s,1H) 7.40 (d, J=8.24 Hz, 1H) 7.47 (d, J=8.13 Hz, 1H) 12.07 (d, J=2.93 Hz,2H); MS (APCI+) m/z 884 (M+H)⁺.

Example 2.3methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-[4-(1,3-dioxan-5-yloxy)phenyl]-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.28-11.98 (m, 2H), 7.45 (d, J=8.1,1H), 7.37 (d, J=8.2, 1H), 7.32-7.23 (m, 3H), 7.21 (s, 1H), 7.12-7.01 (m,2H), 6.62-6.51 (m, 2H), 6.24 (d, J=8.9, 2H), 5.40-5.27 (m, 2H),5.18-5.09 (m, 2H), 4.72 (d, J=6.1, 1H), 4.67 (d, J=6.2, 1H), 4.06 (t,J=8.4, 2H), 4.01-3.75 (m, 7H), 3.68-3.58 (m, 2H), 3.52 (d, J=15.9, 6H),2.28-1.83 (m, 12H), 1.74-1.62 (m, 2H), 0.93-0.73 (m, 12H); MS (ESI+) m/z934.5 (M+H)⁺.

Example 2.4methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-[4-(1,3-dioxolan-4-ylmethoxy)phenyl]-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.27-11.95 (m, 2H), 7.43 (d, J=8.1,1H), 7.35 (d, J=8.2, 1H), 7.32-7.22 (m, 3H), 7.19 (s, 1H), 7.03 (t,J=7.4, 2H), 6.59-6.47 (m, 2H), 6.23 (d, J=8.8, 2H), 5.39-5.27 (m, 2H),5.16-5.04 (m, 2H), 4.83 (d, J=2.6, 1H), 4.74 (s, 1H), 4.22-4.12 (m, 1H),4.04 (t, J=8.3, 2H), 3.88 (t, J=7.5, 1H), 3.83-3.67 (m, 6H), 3.57-3.47(m, 7H), 2.29-1.80 (m, 12H), 1.74-1.60 (m, 2H), 0.93-0.71 (m, 12H); MS(ESI+) m/z 934.4 (M+H)⁺.

Example 2.5methyl{(2S)-1-[(2S)-2-{6-[(2R,5R)-1-{4-[(3-ethyloxetan-3-yl)methoxy]-3,5-difluorophenyl}-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-6-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ 12.30-12.02 (m, 2H), 7.47 (d, J=8.3, 1H),7.40 (d, J=8.3, 1H), 7.34-7.16 (m, 4H), 7.06 (t, J=7.0, 2H), 5.98 (d,J=12.3, 2H), 5.46-5.30 (m, 2H), 5.24-5.05 (m, 2H), 4.29 (d, J=5.5, 2H),4.21 (d, J=5.8, 2H), 4.05 (t, J=8.2, 2H), 3.90-3.72 (m, 6H), 3.52 (s,6H), 2.27-1.81 (m, 12H), 1.73-1.60 (m, 4H), 0.91-0.69 (m, 15H); MS(ESI+) m/z 982.4 (M+H)⁺.

Example 2.6methyl{(2S)-1-[(2S)-2-(6-{(2R,5R)-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-6-yl}-[2,3,5,6-tetrafluoro-4-(piperidin-1-yl)phenyl]pyrrolidin-2-yl}-1H-benzimidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ 12.10 (dd, J=58.0, 37.7, 2H), 7.52-7.21 (m,6H), 7.07 (t, J=8.1, 2H), 5.52-5.29 (m, 2H), 5.17-5.03 (m, 2H),4.12-3.93 (m, 2H), 3.88-3.66 (m, 4H), 3.53 (s, 6H), 2.87-2.71 (m, 4H),2.27-1.76 (m, 14H), 1.50-1.32 (m, 6H), 0.93-0.70 (m, 12H); MS (ESI+) m/z987.3 (M+H)⁺.

Example 2.7methyl{(2S)-1-[(2S)-2-{6-[(2R,5R)-1-[3-fluoro-4-(methylsulfonyl)phenyl]-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-6-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.81-0.97 (m, 12H), 1.30 (s, 2H), 1.82(d, J=4.2 Hz, 2H), 1.90-2.35 (m, 12H), 3.60 (s, 6H), 3.88 (s, 3H), 4.13(t, J=8.3 Hz, 2H), 5.20 (t, J=7.3 Hz, 2H), 5.62 (s, 2H), 6.26-6.40 (m,J=9.5 Hz, 2H), 7.15 (d, J=7.0 Hz, 2H), 7.30 (s, 1H), 7.32-7.45 (m, 4H),7.49 (d, J=8.2 Hz, 1H), 7.56 (d, J=8.1 Hz, 1H), 12.16 (s, 2H); MS (ESI+)m/z 928.4 (M+H)⁺, (ESI−) m/z 926.3 (M−H)⁻.

Example 2.8methyl{(2S)-1-[(2S)-2-{6-[(2R,5R)-1-{4-[acetyl(tert-butyl)amino]-3-fluorophenyl}-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-6-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

Starting from4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-N-tert-butyl-2-fluoroaniline,the initial product of the sequence outlined above wasmethyl{(2S)-1-[(2S)-2-{6-[(2R,5R)-1-[4-(tert-butylamino)-3-fluorophenyl]-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-6-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate(ACD Name v12). The N-acetyl group was added by reaction with aceticanhydride/pyridine to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.73-0.90 (m, 12H), 1.13 (d, J=5.20 Hz, 9H), 1.37-1.44(m, 4H), 1.62-1.72 (m, 2H), 1.92-2.02 (m, 9H), 2.10-2.26 (m, 5H),2.51-2.58 (m, 2H), 3.52 (s, 6H), 3.73-3.85 (m, 4H), 3.98-4.12 (m, 2H),5.09-5.17 (m, 2H), 5.36-5.48 (m, 3H), 6.08-6.18 (m, 3H), 6.74-6.87 (m,1H), 7.08 (dd, J=13.72, 8.29 Hz, 3H), 7.20 (s, 1H), 7.24-7.31 (m, 4H),7.40 (d, J=8.24 Hz, 1 H), 7.48 (d, J=8.13 Hz, 1H), 12.01 (s, 1H), 12.17(s, 1H); MS (ESI+) m/z 964 (M+H)⁺.

Example 2.9methyl{(2S)-1-[(2S)-2-{6-[(2R,5R)-1-[3,5-difluoro-4-(4-methylpiperidin-1-yl)phenyl]-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-6-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrol1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.75-0.90 (m, 12H), 1.05-1.18 (m, 2H),1.24-1.37 (m, 2 H), 1.45-1.54 (m, 2H), 1.62-1.73 (m, 2H), 1.84-2.05 (m,7H), 2.12-2.25 (m, 5H), 2.69-2.81 (m, 4H), 3.52 (s, 6H), 3.77-3.86 (m,4H), 4.05 (t, J=8.35 Hz, 2H), 5.10-5.18 (m, 2H), 5.35 (q, J=7.34 Hz,2H), 5.87 (d, J=12.69 Hz, 2H), 7.02-7.10 (m, 2H), 7.19 (s, 1H),7.24-7.32 (m, 3H), 7.39 (d, J=8.24 Hz, 1H), 7.47 (d, J=8.13 Hz, 1H),12.06 (d, J=20.93 Hz, 2H); MS (ESI+) m/z 966 (M+H)⁺.

Example 2.10methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-{3,5-difluoro-4-[4-(3-phenylpropyl)piperidin-1-yl]phenyl}-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.72-0.95 (m, 12H), 1.00-1.31 (m, 9H),1.46-1.59 (m, 4 H), 1.61-1.79 (m, 2H), 1.83-2.08 (m, 6H), 2.11-2.27 (m,4H), 2.77 (s, 4H), 3.54 (s, 6H), 3.82 (s, 4H), 4.06 (t, J=8.46 Hz, 2H),5.08-5.19 (m, 2H), 5.28-5.46 (m, 2H), 5.88 (d, J=12.79 Hz, 2 H),7.01-7.10 (m, 2H), 7.10-7.33 (m, 9H), 7.40 (d, J=8.13 Hz, 1H), 7.48 (d,J=8.13 Hz, 1H), 11.71-12.51 (m, 2H); MS (ESI+) m/z 1069 (M+H)⁺; MS(ESI−) m/z 1067 (M−H)⁻.

Example 2.11methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-[4-(8-azaspiro[4.5]dec-8-yl)-3,5-difluorophenyl]-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.73-0.93 (m, 12H), 1.29-1.43 (m, 9H),1.52 (t, J=6.83 Hz, 5H), 1.68 (s, 2H), 1.81-2.08 (m, 6H), 2.10-2.26 (m,4H), 2.75 (s, 4H), 3.54 (s, 6H), 3.82 (s, 4 H), 4.06 (t, J=8.40 Hz, 2H),5.09-5.19 (m, 2H), 5.29-5.46 (m, 2H), 5.88 (d, J=12.58 Hz, 2H),7.03-7.11 (m, 2H), 7.20 (s, 1H), 7.25-7.33 (m, 3H), 7.40 (d, J=8.24 Hz,1H), 7.49 (d, J=8.24 Hz, 1H), 11.63-12.57 (m, 2H); MS (ESI+) m/z 1005(M+H)⁺; MS (ESI−) m/z 1003 (M−H)⁻.

Example 2.12methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-{3,5-difluoro-4-[4-(2-naphthyl)piperidin-1-yl]phenyl}-5-{2-[2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.76-0.91 (m, 12H), 1.24 (d, J=2.28 Hz,2H), 1.63-2.08 (m, 12H), 2.20 (s, 4H), 2.86-3.19 (m, 5H), 3.53 (s, 6H),3.82 (s, 4H), 4.06 (t, J=8.29 Hz, 2H), 5.10-5.22 (m, 2H), 5.32-5.48 (m,2H), 5.93 (d, J=12.90 Hz, 2H), 7.03-7.16 (m, 2H), 7.19-7.36 (m, 4 H),7.39-7.55 (m, 5H), 7.69-7.89 (m, 4H), 11.71-12.63 (m, 2H); MS (ESI+) m/z1077 (M+H)⁺; MS (EST−) m/z 1075 (M−H)⁻.

Example 2.13methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-{3,5-difluoro-4-[4-(pyridin-2-yl)piperidin-1-yl]phenyl}-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.71-1.02 (m, 12H), 1.62-1.83 (m, 6H),1.81-2.08 (m, 7 H), 2.10-2.29 (m, 4H), 2.47-2.63 (m, 2H), 2.81-3.07 (m,4H), 3.53 (s, 6H), 3.82 (s, 4H), 4.06 (t, J=8.89 Hz, 2H), 5.10-5.21 (m,2H), 5.31-5.47 (m, 2H), 5.91 (d, J=12.69 Hz, 2H), 7.04-7.13 (m, 2H),7.14-7.20 (m, 1H), 7.20-7.34 (m, 5H), 7.41 (d, J=8.24 Hz, 1H), 7.49 (d,J=8.35 Hz, 1H), 7.62-7.72 (m, 1H), 8.45 (d, J=4.55 Hz, 1H), 11.74-12.57(m, 2H); MS (ESI+) m/z 1028 (M+H)⁺; MS (ESI−) m/z 1026 (M−H)⁻.

Example 2.14methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-(3,5-difluoro-4-{4-[4-(trimethylsilyl)phenyl]piperidin-1-yl}phenyl)-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.20 (s, 9H), 0.74-0.94 (m, 12H),1.59-1.75 (m, 6H), 1.83-2.09 (m, 7H), 2.13-2.29 (m, 4H), 2.44-2.59 (m,2H), 2.84-3.15 (m, 4H), 3.53 (s, 6H), 3.82 (s, 4H), 4.06 (t, J=8.46 Hz,2H), 5.15 (d, J=3.04 Hz, 2H), 5.31-5.47 (m, 2H), 5.92 (d, J=12.79 Hz, 2H), 7.04-7.14 (m, 2H), 7.21 (d, J=7.92 Hz, 3H), 7.27-7.37 (m, 3H),7.37-7.45 (m, 3H), 7.50 (d, J=8.02 Hz, 1H), 12.10 (d, J=17.57 Hz, 2H);MS (ESI+) m/z 1099 (M+H)⁺; MS (ESI−) m/z 1097 (M−H)⁻.

Example 2.15methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-{3,5-difluoro-4-[4-(1-naphthyl)piperidin-1-yl]phenyl}-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.74-0.94 (m, 12H), 1.64-2.05 (m, 12H),2.13-2.29 (m, 3 H), 2.45-2.62 (m, 2H), 2.90-3.01 (m, J=11.06 Hz, 2H),3.08-3.25 (m, 2H), 3.53 (s, 6H), 3.82 (s, 4H), 4.06 (t, J=8.29 Hz, 2H),5.08-5.23 (m, 2H), 5.32-5.52 (m, 2H), 5.94 (d, J=12.69 Hz, 2H),7.04-7.17 (m, 2H), 7.20-7.37 (m, 4H), 7.38-7.59 (m, 6H), 7.75 (d, J=8.35Hz, 1H), 7.86-7.95 (m, 1H), 8.14 (d, J=8.24 Hz, 1H), 11.61-12.69 (m,2H); MS (ESI+) m/z 1077 (M+H)⁺; (ESI−) m/z 1075 (M−H)⁻.

Example 2.16methyl{(2S)-1-[(2S)-2-{5-[(5R)-1-[4-(3,5-dimethylpiperidin-1-yl)-3,5-difluorophenyl]-5-{6-fluoro-2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-6-fluoro-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.64-0.94 (m, 18H) 1.56-1.73 (m, 4H)1.75-1.93 (m, 6H) 1.95-2.06 (m, 6H) 2.12-2.26 (m, 4H) 2.69-2.79 (m, 1H)3.20-3.29 (m, 1H) 3.53 (s, 6H) 3.74-3.89 (m, 4H) 3.97-4.10 (m, 2H)5.05-5.19 (m, 2H) 5.48-5.62 (m, 2H) 5.87 (dd, J=11.49, 7.92 Hz, 2H) 7.02(dd, J=3.90, 1.95 Hz, 1H) 7.12 (d, J=6.83 Hz, 1H) 7.26-7.37 (m, 3H) 7.40(dd, J=11.11, 6.02 Hz, 1H) 12.08-12.16 (m, 1H) 12.23-12.31 (m, 1H); MS(APCI+) m/z 1016 (M+H)⁺.

Example 2.17methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-(3,5-difluoro-4-{4-[4-(trifluoromethyl)phenyl]piperazin-1-yl}phenyl)-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.69-0.96 (m, 14H) 1.10-1.29 (m, 2H)1.69 (m, 2H) 1.99 (m, 4H) 2.20 (m, 2H) 2.99 (m, 6H) 3.22-3.26 (m, 6H)3.54 (s, 6H) 3.82 (m, 6H) 5.15 (m, 2H) 5.39 (m, 2H) 5.95 (m, 2H) 7.03(d, J=8.78 Hz, 2H) 7.22 (m, 2H) 7.24-7.36 (m, 2H) 7.40-7.56 (m, 4H)12.06 (s, 2H); MS (ESI+) m/z 1096.4, (ESI−) m/z 1094.3.

The following Example compounds 3.1-3.51 can be made from theappropriate listed intermediates following the methods of GeneralProcedures 12/12A.

Intermediate Amines:

-   (S)-6,6′-((2R,5R)-1-(4-(pyridin-2-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(3-chloro-4-(trifluoromethoxy)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(4-(2-methoxyethoxy)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(4-chlorophenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(biphenyl-4-yl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S,S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((2S,4S)-4-methoxypyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S,S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((2S,4S)-4-fluoropyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S,S)-6,6′-((2R,5R)-1-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(2-((2S,4S)-4-fluoropyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S,S)-6,6′-((2R,5R)-1-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(2-((2S,4S)-4-methoxypyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(2-((S)-5,5-dimethylpyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S,S)-6,6′-((2R,5R)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(2-((2S,4S)-4-fluoropyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2S,5S)-1-(4-cyclopropyl-2-fluorophenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(3-fluoro-4-(piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(3-fluoro-4-(4-phenylpiperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(4-phenylpiperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((3S)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-indolin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(2-((S)-4-methylenepyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S,S,S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(4-phenylpiperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((2S,3aS,6aS)-octahydrocyclopenta[b]pyrrol-2-yl)-1H-benzo[d]imidazole);    (S,S,S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((2S,3aS,6aS)-octahydrocyclopenta[b]pyrrol-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(4-phenylpiperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[c]imidazole);-   6,6′-{(2R,5R)-1-[3,5-difluoro-4-(piperidin-1-yl)phenyl]pyrrolidine-2,5-diyl}bis{5-fluoro-2-[(2S)-pyrrolidin-2-yl]-1H-benzimidazole}    (ACD Name v12);-   (S,S,S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-2-((2S,3aS,6aS)-octahydrocyclopenta[b]pyrrol-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(4-(4-fluorophenyl)piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(4-(3-(trimethylsilyl)phenyl)piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(4-(4-(3,4-difluorophenyl)piperidin-1-yl)-3,5-difluorophenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(4-(4-(3,5-difluorophenyl)piperidin-1-yl)-3,5-difluorophenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2S,5R)-1-(2-(4-phenylpiperidin-1-yl)pyrimidin-5-yl)pyrrolidine-2,5-diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2S,5R)-1-(2-(piperidin-1-yl)pyrimidin-5-yl)pyrrolidine-2,5-diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(4-(4-(2,6-difluorophenyl)piperazin-1-yl)-3,5-difluorophenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2S,5S)-1-(4-(4-(2,6-difluorophenyl)piperazin-1-yl)-3,5-difluorophenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);    and-   (S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(4-(4-fluorophenyl)piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole).

Intermediate acids:

-   (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid;-   (S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic    acid;-   (S)-2-cyclohexyl-2-(methoxycarbonylamino)acetic acid;-   (S)-2-cyclopentyl-2-(methoxycarbonylamino)acetic acid;-   (S)-2-(methoxycarbonylamino)-3,3-dimethylbutanoic acid;-   (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid;-   (2S,3S)-3-methoxy-2-(methoxycarbonylamino)butanoic acid;-   (S)-2-(methoxycarbonylamino)-2-((R)-tetrahydrofuran-3-yl)acetic    acid;-   (S)-2-(methoxycarbonylamino)-2-((S)-tetrahydrofuran-3-yl)acetic    acid;-   (S)-2-(2,3-dihydro-1H-inden-2-yl)-2-(methoxycarbonylamino)acetic    acid;-   2-(tert-butoxycarbonylamino)acetic acid;-   2-(methoxycarbonylamino)-3-methylbut-2-enoic acid;-   (S)-tetrahydrofuran-2-carboxylic acid-   (S)-3-ethyl-2-(methoxycarbonylamino)pentanoic acid; and-   (S)-2-(ethoxycarbonylamino)-3-methylbutanoic acid.

Example 3.1methyl{(2S)-1-[(2S)-2-(5-{(2R,5R)-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}-1-[4-(pyridin-2-yl)phenyl]pyrrolidin-2-yl}-1H-benzimidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.28-11.98 (m, 2H), 8.42 (d, J=4.4,1H), 7.70-7.56 (m, 4H), 7.46 (d, J=8.2, 1H), 7.38 (d, J=8.2, 1H), 7.34(s, 1H), 7.30-7.20 (m, 3H), 7.16-7.02 (m, 3H), 6.42 (d, J=8.7, 2H),5.56-5.42 (m, 2H), 5.18-5.06 (m, 2H), 4.03 (t, J=9.3, 2H), 3.88-3.73 (m,4H), 3.52 (s, 6H), 2.25-1.62 (m, 14H), 0.92-0.67 (m, 12H); MS (ESI+) m/z909.5 (M+H)⁺.

Example 3.2methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-[3-chloro-4-(trifluoromethoxy)phenyl]-5-{(2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.31-12.01 (m, 2H), 7.48 (d, J=7.9,1H), 7.40 (d, J=8.2, 1H), 7.34-7.17 (m, 4H), 7.15-6.99 (m, 3H), 6.44 (s,1H), 6.30 (d, J=8.9, 1H), 5.55-5.37 (m, 2H), 5.19-5.04 (m, 2H), 4.04 (t,J=7.8, 2H), 3.89-3.73 (m, 4H), 3.52 (s, 6H), 2.28-1.79 (m, 12H),1.77-1.59 (m, 2H), 0.92-0.64 (m, 12H); MS (ESI+) m/z 950.4 (M+H)⁺.

Example 3.3methyl{(2S)-1-[(2S)-2-(5-{(2R,5R)-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}-1-[4-(2-methoxyethoxy)phenyl]pyrrolidin-2-yl}-1H-benzimidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.27-11.97 (m, 2H), 7.44 (d, J=8.4,1H), 7.36 (d, J=7.7, 1H), 7.33-7.25 (m, 3H), 7.20 (s, 1H), 7.12-7.00 (m,2H), 6.58-6.47 (m, 2H), 6.24 (d, J=9.0, 2H), 5.40-5.27 (m, 2H),5.19-5.08 (m, 2H), 4.06 (t, J=8.3, 2H), 3.88-3.76 (m, 6H), 3.54 (s, 6H),3.51-3.45 (m, 2H), 3.21 (s, 3H), 2.26-1.83 (m, 12H), 1.75-1.64 (m, 2H),0.93-0.74 (m, 12H); MS (ESI+) m/z 906.4 (M+H)⁺.

Example 3.4methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-(4-chlorophenyl)-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.05 (s, 2H), 7.44 (d, J=8.2, 1H), 7.36(d, J=8.1, 1H), 7.31-7.22 (m, 3H), 7.19 (s, 1H), 7.03 (t, J=8.2, 2H),6.94-6.83 (m, 2H), 6.29 (d, J=9.1, 2H), 5.42-5.32 (m, 2H), 5.16-5.04 (m,2H), 4.04 (t, J=8.4, 2H), 3.85-3.75 (m, 4H), 3.51 (s, 6H), 2.25-1.58 (m,14H), 0.90-0.73 (m, 12H); MS (ESI+) m/z 866.4 (M+H)⁺.

Example 3.5methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-(biphenyl-4-yl)-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ 12.11-11.66 (m, 2H), 7.47 (d, J=8.3, 1H),7.43-7.33 (m, 4H), 7.32-7.19 (m, 7H), 7.17-7.06 (m, 3H), 6.43 (d, J=8.8,2H), 5.52-5.41 (m, 2H), 5.18-5.09 (m, 2H), 4.05 (t, J=8.2, 2H),3.87-3.76 (m, 4H), 3.53 (s, 6H), 2.25-2.11 (m, 4H), 2.05-1.62 (m, 10H),0:91-0.74 (m, 12H); MS (ESI+) m/z 908.5 (M+H)⁺.

Example 3.6dimethyl([(2R,5R)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis{1H-benzimidazole-5,2-diyl(2S)pyrrolidine-2,1-diyl[1S)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethane-2,1-diyl]})biscarbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.07 (s, 9H) 1.22-1.32 (m, 2H) 1.42-1.57(m, 4H) 1.64-1.72 (m, 2H) 1.82 (dd, J=21.90, 10.63 Hz, 4H) 1.92-2.02 (m,4H) 2.10-2.25 (m, 4H) 2.90-2.99 (m, 1H) 3.04-3.19 (m, 4H) 3.53 (s, 6H)3.56-3.63 (m, 1H) 3.66-3.79 (m, 4H) 3.83 (d, J=3.04 Hz, 4H) 4.14 (q,J=8.10 Hz, 2H) 5.07-5.15 (m, 2H) 5.33-5.40 (m, 2H) 6.24 (d, J=8.89 Hz,2H) 6.85-6.94 (m, 2H) 7.09 (dd, J=14.10, 8.46 Hz, 2H) 7.16-7.22 (m, 2H)7.30-7.41 (m, 3H) 7.44 (d, J=9.43 Hz, 1H) 11.99-12.12 (m, 2H); MS (ESI+)m/z 972.5 (M+H)⁺.

Example 3.7methyl{(2S)-1-[(2S,4S)-2-{5-[(2R,5R)-1-[3,5-difluoro-4-(piperidin-1-yl)phenyl]-5-{2-[(2S,4S)-4-methoxy-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}-4-methoxypyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.76-0.87 (m, 12H) 1.35-1.40 (m, 2H)1.45 (s, 4H) 1.66-1.72 (m, 2H) 1.95 (dd, J=13.28, 7.17 Hz, 2H) 2.14 (td,J=12.32, 5.87 Hz, 2H) 2.41-2.46 (m, 2H) 2.76 (s, 4H) 3.03-3.18 (m, 2H)3.25 (d, J=3.66 Hz, 6H) 3.54 (s, 6H) 3.64 (td, J=11.14, 5.65 Hz, 2 H)4.05-4.13 (m, 4H) 4.19-4.27 (m, 2H) 5.10-5.16 (m, 2H) 5.31-5.39 (m, 2H)5.88 (d, J=12.66 Hz, 2H) 7.06 (t, J=8.47 Hz, 2H) 7.21-7.31 (m, 4H) 7.41(d, J=8.09 Hz, 1H) 7.48 (dd, J=8.39, 1.83 Hz, 1H) 11.81-11.91 (m, 2H);MS (ESI+) m/z 1011.6 (M+H)⁺.

Example 3.8methyl{(2S)-1-[(2S,4S)-2-{5-[(2R,5R)-1-[3,5-difluoro-4-(piperidin-1-yl)phenyl]-5-{2-[(2S,4S)-4-fluoro-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}-4-fluoropyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.80-0.99 (m, 12H) 1.38 (d, J=4.73 Hz,2H) 1.45 (s, 4H) 1.64-1.74 (m, 2H) 2.00-2.08 (m, 2H) 2.37-2.45 (m, 2H)2.76 (s, 4H) 3.08-3.19 (m, 2H) 3.55 (s, 6H) 3.99-4.26 (m, 6H) 5.30-5.39(m, 4H) 5.47 (d, J=53.41 Hz, 4H) 5.89 (d, J=12.66 Hz, 2H) 7.02-7.11 (m,2H) 7.27 (d, J=25.02 Hz, 2H) 7.41 (d, J=8.09 Hz, 3H) 7.47 (d, J=7.93 Hz,1H) 11.85 (d, J=31.74 Hz, 2H); MS (ESI+) m/z 987.5 (M+H)⁺.

Example 3.9methyl{(2S)-1-[(2S,4S)-4-fluoro-2-{5-[(2R,5R)-5-{2-[(2S,4S)-4-fluoro-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}-1-(4-fluorophenyl)pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.82-0.98 (m, 12H) 1.68-1.77 (m, 2H)1.91-2.09 (m, 4H) 2.36-2.44 (m, 2H) 2.59-2.66 (m, 2H) 3.52-3.57 (m, 6H)3.72-3.98 (m, 2H) 4.07-4.18 (m, 4H) 5.19 (t, J=8.08 Hz, 1H) 5.31-5.44(m, 4H) 5.48-5.57 (m, 1H) 6.24-6.31 (m, 2H) 6.70-6.78 (m, 2H) 7.02-7.12(m, 2H) 7.17 (s, 1H) 7.24-7.34 (m, 2H) 7.39 (t, J=7.92 Hz, 2H) 7.47 (dd,J=20.38, 8.35 Hz, 1H) 11.78-12.06 (m, 2H); MS (ESI+) m/z 886.4 (M+H)⁺.

Example 3.10methyl{(2S)-1-[(2S,4S)-2-{5-[(2R,5R)-1-(4-fluorophenyl)-5-{2-[(2S,4S)-4-methoxy-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}-4-methoxypyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.77-0.90 (m, 12H) 1.66-1.76 (m, 2H)1.88-2.01 (m, 2H) 2.06-2.19 (m, 2H) 2.54-2.62 (m, 2H) 3.25 (d, J=5.86Hz, 6H) 3.54 (s, 6H) 3.59-3.72 (m, 2H) 3.97-4.14 (m, 6H) 4.16-4.30 (m,2H) 5.05-5.19 (m, 2H) 5.36 (d, J=3.25 Hz, 2H) 6.28 (dd, J=7.26, 4.34 Hz,2H) 6.69-6.79 (m, 2H) 7.04 (d, J=8.57 Hz, 2H) 7.22-7.33 (m, 4H) 7.38 (d,J=8.02 Hz, 1H) 7.45 (d, J=8.24 Hz, 1H) 11.81 (s, 2H); MS (ESI+) m/z910.4 (M+H)⁺.

Example 3.11methyl{(2S)-1-[(5S)-5-{5-[(2R,5R)-1-(4-tert-butylphenyl)-5-(2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-5,5-dimethylpyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl)-2,2-dimethylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.81 (d, J=6.61 Hz, 6H) 0.89 (d, J=6.72Hz, 6H) 1.07 (s, 9H) 1.38 (s, 6H) 1.62 (s, 6H) 1.68-1.77 (m, 4H) 1.82(s, 2H) 1.94 (dd, J=13.61, 6.78 Hz, 2H) 2.10-2.18 (m, 2H) 2.27 (dd,J=4.12, 2.60 Hz, 2H) 3.15 (d, J=3.36 Hz, 6H) 3.96-4.03 (m, 2H) 5.30-5.43(m, 6H) 6.24-6.31 (m, 2H) 6.70 (t, J=6.67 Hz, 2H) 6.84-6.91 (m, 2H)7.05-7.13 (m, 2H) 7.24 (s, 1H) 7.36 (d, J=1.08 Hz, 1H) 7.40 (d, J=7.59Hz, 1H) 7.49 (d, J=8.78 Hz, 1H) 12.16 (d, J=29.28 Hz, 2H); MS (ESI+) m/z944.5 (M+H)⁺.

Example 3.12methyl{(2S)-1-[(2S,4S)-2-{5-[(2R,5R)-1-(4-tert-butylphenyl)-5-{2-[(2S,4S)-4-fluoro-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}-4-fluoropyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.79-0.97 (m, 12H) 1.07 (s, 9H)1.66-1.75 (m, 2H) 1.99-2.08 (m, 2H) 2.40 (dd, J=17.02, 3.04 Hz, 2H)3.09-3.21 (m, 4H) 3.55 (s, 6H) 4.05-4.13 (m, 4H) 4.16-4.27 (m, 2H) 5.35(dd, J=8.51, 3.09 Hz, 4H) 5.46 (d, J=53.24 Hz, 2H) 6.23-6.29 (m, 2H)6.91 (d, J=8.89 Hz, 2H) 7.03-7.11 (m, 2H) 7.23 (d, J=3.47 Hz, 1H) 7.28(s, 1H) 7.39 (dd, J=8.08, 4.72 Hz, 3H) 7.44 (d, J=8.57 Hz, 1H) 11.80 (d,J=20.06 Hz, 2H); MS (ESI+) m/z 924.4 (M+H)⁺.

Example 3.13methyl{(2S,3R)-1-[(2S)-2-{5-[(2S,5S)-1-(4-cyclopropyl-2-fluorophenyl)-5-(2-{(2S)-1-[N-(methoxycarbonyl)-O-methyl-L-threonyl]pyrrolidin-2-yl}-1H-benzimidazol-5-yl)pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methoxy-1-oxobutan-2-yl}carbamate

¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.35-0.57 (m, 2H) 0.66-0.85 (m, 2H)1.07-1.17 (m, 7H) 1.59-1.69 (m, 1H) 1.82 (s, 2H) 1.95-2.12 (m, 5H)2.13-2.33 (m, 5H) 3.17-3.35 (m, 6H) 3.48-3.65 (m, 6H) 3.85-3.95 (m, 4H)4.29-4.38 (m, 2H) 5.11-5.25 (m, 2H) 5.58 (s, 2H) 6.44-6.57 (m, 2H)6.59-6.70 (m, 1H) 7.07-7.19 (m, 2H) 7.25-7.32 (m, 2H) 7.35-7.41 (m, 2H)7.45 (d, J=8.24 Hz, 2H) 12.05 (d, J=16.63 Hz, 2H); MS (ESI+) m/z 922.4(M+H)⁺, (ESI−) m/z 920.3 (M−H)⁻.

Example 3.14tert-butyl{2-[(2S)-2-(5-{(2S,5S)-5-{2-[(2S)-{[(tert-butoxycarbonyl)amino]acetyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}-1-[3-fluoro-4-(piperidin-1-yl)phenyl]pyrrolidin-2-yl}-1H-benzimidazol-2-yl)pyrrolidin-1-yl]-2-oxoethyl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.16-1.43 (m, 18H) 1.42-2.27 (m, 14H)2.58-2.70 (m, 5 H) 3.38-4.02 (m, 9H) 5.14 (s, 2H) 5.33 (s, 3H) 6.04 (s,2H) 6.74 (s, 3H) 7.04-7.60 (m, 7H) 11.83-12.43 (m, 2H); MS (ESI+) m/z933.4 (M+H)⁺, (ESI−) m/z 931.4 (M−H)⁻.

Example 3.15methyl{(2S)-1-[(2S)-2-{5-[(2S,5S)-1-[3-fluoro-4-(piperidin-1-yl)phenyl]-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.73-0.93 (m, 12H) 1.32-1.57 (m, 6H)1.58-2.06 (m, 14 H) 2.18 (s, 4H) 2.67 (dd, J=3.69, 1.95 Hz, 4H)3.75-3.87 (m, 6H) 4.07 (t, 2H) 5.13 (s, 2H) 5.37 (dd, J=6.02, 2.11 Hz,2H) 6.04 (s, 2H) 6.65 (s, 1H) 7.09 (s, 2H) 7.16-7.23 (m, 1H) 7.23-7.48(m, 5H) 12.01 (s, 2H); MS (ESI+) m/z 933.5 (M+H)⁺, (ESI−) m/z 931.4(M−H)⁻.

Example 3.16methyl{(2S,3R)-1-[(2S)-2-{5-[(2S,5S)-1-[3-fluoro-4-(piperidin-1-yl)phenyl]-5-(2-{(2S)-1[N-(methoxycarbonyl)-O-methyl-L-threonyl]pyrrolidin-2-yl}-1H-benzimidazol-5-yl)pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methoxy-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.00-1.14 (m, 6H) 1.33-1.55 (m, 6H)1.59-2.28 (m, 14H) 2.58-2.71 (m, 4H) 3.10-3.27 (m, 6H) 3.54 (d, J=1.41Hz, 6H) 3.71-3.90 (m, 6H) 4.21-4.33 (m, 2H) 5.02-5.22 (m, 2H) 5.37 (dd,J=6.02, 2.01 Hz, 2H) 6.04 (s, 2H) 6.58-6.84 (m, 1H) 7.06 (d, J=22.88 Hz,2H) 7.16-7.32 (m, 2H) 7.39 (d, J=8.13 Hz, 2H) 11.90-12.34 (m, 2H); MS(ESI+) m/z 965.5 (M+H)⁺, (ESI−) m/z 963.3 (M−H)⁻.

Example 3.17dimethyl{[(2S,5S)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis[1H-benzimidazole-5,2-diyl(2S)pyrrolidine-2,1-diyl(3-methyl-1-oxobut-2-ene-1,2-diyl)]})biscarbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.87-1.20 (m, 9H) 1.60-1.77 (m, 14H)1.80-2.35 (m, 10H) 3.16-3.79 (m, 10H) 5.14 (s, 2H) 5.37 (s, 2H) 6.24 (d,J=3.04 Hz, 2H) 6.92 (dd, J=8.57, 6.29 Hz, 2H) 7.11 (s, 3H) 7.31 (s, 1H)7.39 (d, J=8.13 Hz, 1H) 7.50 (d, J=8.24 Hz, 1H) 8.89 (d, 2H) 11.64-12.14(m, 2H); MS (ESI+) m/z 884.5 (M+H)⁺, 918.4 (M+NH₃+NH₄)⁺.

Example 3.18dimethyl({(2R,5R)-1-[3,5-difluoro-4-(piperidin-1-yl)phenyl]pyrrolidine-2,5-diyl}bis{1H-benzimidazole-5,2-diyl(2S)pyrrolidine-2,1-diyl[(1S)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethane-2,1-diyl]})biscarbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.13-1.33 (m, 4H) 1.36-1.57 (m, 10H)1.65-1.71 (m, 2H) 1.79-1.90 (m, 2H) 1.96-2.03 (m, 4H) 2.13-2.26 (m, 4H)2.76 (s, 4H) 2.93-3.15 (m, 4H) 3.53 (s, 6H) 3.62 (dd, J=10.03, 2.01 Hz,2H) 3.68-3.80 (m, 4H) 3.81-3.88 (m, 4H) 4.11-4.18 (m, 2H) 5.10-5.18 (m,2H) 5.33-5.40 (m, 2H) 5.82-5.92 (m, 2H) 7.09 (dd, J=12.52, 8.29 Hz, 2H)7.17-7.24 (m, 2H) 7.35 (t, J=8.35 Hz, 2H) 7.41 (d, J=7.92 Hz, 1H) 7.47(d, J=6.94 Hz, 1H) 12.05 (d, J=1.73 Hz, 1H) 12.15 (d, J=2.17 Hz, 1H); MS(ESI+) m/z 1035.5 (M+H)⁺.

Example 3.19methyl{(2S)-1-[(3S)-3-{5-[(2R,5R)-1-[3,5-difluoro-4-(piperidin-1-yl)phenyl]-5-{2-[(3S)-2-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-2-azabicyclo[2.2.1]hept-3-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}-2-azabicyclo[2.2.1]hept-2-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.80-0.87 (m, 6H) 0.93 (t, J=7.05 Hz,6H) 1.36-1.48 (m, 10H) 1.49-1.57 (m, 2H) 1.64-1.70 (m, 4H) 1.72-1.79 (m,4H) 1.84-1.90 (m, 2H) 1.92-1.98 (m, 2H) 2.61 (s, 2H) 2.72-2.78 (m, 4H)3.54 (s, 6H) 4.10-4.17 (m, 2H) 4.50 (s, 2H) 4.59 (d, J=7.48 Hz, 2H)5.32-5.41 (m, 2H) 5.89 (d, J=12.58 Hz, 2H) 7.07 (d, J=7.70 Hz, 2H) 7.18(d, J=9.65 Hz, 2H) 7.21 (s, 1H) 7.32 (s, 1H) 7.40 (d, J=8.13 Hz, 1H)7.49 (d, J=8.02 Hz, 1H) 12.01 (dd, J=12.58, 1.08 Hz, 2H); MS (ESI+) m/z1003.4 (M+H)⁺.

Example 3.20methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-[3-fluoro-4-(4-phenylpiperidin-1-yl)phenyl]-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.77-0.90 (m, 12H) 1.66-1.75 (m, 8H)1.86-1.95 (m, 2H) 1.96-2.05 (m, 4H) 2.14-2.24 (m, 4H) 3.04-3.14 (m, 4H)3.53 (s, 6H) 3.77-3.86 (m, 4H) 4.06 (t, J=8.40 Hz, 2H) 5.11-5.17 (m, 2H)5.35 (q, J=6.83 Hz, 2H) 6.05-6.12 (m, 2H) 6.71 (ddd, J=13.99, 9.22, 4.34Hz, 1H) 7.07 (t, J=7.05 Hz, 2H) 7.16 (t, J=6.94 Hz, 2H) 7.20-7.32 (m,8H) 7.39 (d, J=8.13 Hz, 1H) 7.47 (d, J=8.46 Hz, 1H) 12.05 (d, J=5.64 Hz,2H); MS (ESI+) m/z 1009.4 (M+H)⁺.

Example 3.21methyl[(1S)-2-[(2S)-2-{5-[(2R,5R)-1-[3-fluoro-4-(4-phenylpiperidin-1-yl)phenyl]-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl]carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.76-0.92 (m, 6H) 1.47-1.57 (m, 2H)1.65-1.76 (m, 8H) 1.81-1.94 (m, 2H) 1.94-2.04 (m, 4H) 2.15-2.23 (m, 4H)3.03-3.15 (m, 4H) 3.53 (s, 6H) 3.57-3.67 (m, 2H) 3.70-3.79 (m, 2H)3.79-3.89 (m, 4H) 4.07-4.20 (m, 2H) 5.10-5.19 (m, 2H) 5.32-5.41 (m, 2H)6.04-6.11 (m, 2H) 6.66-6.75 (m, 1H) 7.03-7.36 (m, 12H) 7.39 (dd, J=8.78,1.63 Hz, 1H) 7.46 (t, J=8.78 Hz, 1H) 12.02-12.14 (m, 2H); MS (APCI+) m/z1051 (M+H)⁺.

Example 3.22dimethyl({(2R,5R)-1-[3,5-difluoro-4-(4-phenylpiperidin-1-yl)phenyl]pyrrolidine-2,5-diyl}bis{1H-benzimidazole-5,2-diyl(2S)pyrrolidine-2,1-diyl[(1S)-1-cyclohexyl-2-oxoethane-2,1-diyl]})biscarbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.81-1.14 (m, 11H) 1.40-1.71 (m, 20H)1.94-2.05 (m, 4 H) 2.14-2.26 (m, 4H) 2.83-2.91 (m, 2H) 2.93-3.02 (m, 2H)3.52 (d, J=3.80 Hz, 6H) 3.76-3.87 (m, 4H) 4.08 (q, J=8.53 Hz, 2H) 5.14(d, J=5.86 Hz, 2H) 5.33-5.45 (m, 2H) 5.85-5.98 (m, 2H) 7.05-7.31 (m,11H) 7.42 (d, J=9.76 Hz, 1H) 7.49 (d, J=8.24 Hz, 1H) 12.00 (s, 1H) 12.16(d, J=3.58 Hz, 1H); MS (ESI+) m/z 1107.5 (M+H)⁺.

Example 3.23dimethyl({(2R,5R)-1-[3,5-difluoro-4-(4-phenylpiperidin-1-yl)phenyl]pyrrolidine-2,5-diyl}bis{1H-benzimidazole-5,2-diyl(2S)pyrrolidine-2,1-diyl[(1S)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethane-2,1-diyl]})biscarbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.14-1.37 (m, 4H) 1.43-1.57 (m, 4H)1.61-1.72 (m, 6H) 1.77-1.91 (m, 2H) 1.96-2.05 (m, 4H) 2.14-2.25 (m, 4H)2.87-3.02 (m, 6H) 3.06-3.22 (m, 2H) 3.53 (s, 6H) 3.58-3.67 (m, 2H)3.68-3.79 (m, 5H) 3.81-3.89 (m, 4H) 4.11-4.19 (m, 2H) 5.14 (dd, J=7.32,2.98 Hz, 2H) 5.34-5.42 (m, 2H) 5.85-5.95 (m, 2H) 7.06-7.17 (m, 3H)7.19-7.29 (m, 6H) 7.35 (t, J=9.05 Hz, 2H) 7.42 (d, J=8.57 Hz, 1H) 7.47(d, J=8.78 Hz, 1H) 12.05 (s, 1H) 12.16 (d, J=1.41 Hz, 1H); MS (ESI+) m/z1111.5 (M+H)⁺.

Example 3.24dimethyl({(2R,5R)-1-[3,5-difluoro-4-(4-phenylpiperidin-1-yl)phenyl]pyrrolidine-2,5-diyl}bis{1H-benzimidazole-5,2-diyl(2S)pyrrolidine-2,1-diyl[(1S)-1-cyclopentyl-2-oxoethane-2,1-diyl]})biscarbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.16-1.28 (m, 4H) 1.31-1.54 (m, 10H)1.55-1.73 (m, 10 H) 1.95-2.06 (m, 4H) 2.09-2.24 (m, 7H) 2.85-3.07 (m,4H) 3.53 (s, 6H) 3.82 (s, 4H) 4.15 (t, J=8.51 Hz, 2H) 5.11-5.18 (m, 2H)5.34-5.43 (m, 2H) 5.92 (d, J=12.69 Hz, 2H) 7.06-7.18 (m, 3 H) 7.19-7.31(m, 6H) 7.37-7.45 (m, 3H) 7.50 (d, J=8.35 Hz, 1H) 12.01 (s, 1H) 12.08(s, 1H); MS (ESI+) m/z 1079.4 (M+H)⁺.

Example 3.25methyl{(2R)-1-[(2S)-2-{5-[(2R,5R)-1-[3,5-difluoro-4-(piperidin-1-yl)phenyl]-5-{2-[(2S)-1-{(2R)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-2,3-dihydro-1H-indol-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}-2,3-dihydro-1H-indol-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.90 (dd, J=31.72, 6.23 Hz, 12H)1.31-1.51 (m, 7H) 1.52-1.70 (m, 2H) 2.06-2.29 (m, 4H) 2.74 (s, 6H) 3.08(d, J=15.40 Hz, 6H) 3.69-3.89 (m, 2H) 4.27 (s, 1H) 5.26-5.39 (m, 2H)5.77-6.01 (m, 4H) 7.01-7.33 (m, 12H) 7.37-7.53 (m, 2H) 8.12-8.25 (m, 2H)12.34 (d, J=42.07 Hz, 2H); MS (ESI+) m/z 1047.4 (M+H)⁺.

Example 3.26methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-(4-tert-butylphenyl)-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-4-methylidenepyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}-4-methylidenepyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.74-0.92 (m, 12H) 1.07 (s, 9H) 1.68 (s,2H) 1.91 (ddd, J=14.64, 7.64, 7.43 Hz, 2H) 2.61-2.75 (m, 2H) 2.97-3.09(m, 2H) 3.13 (s, 1H) 3.54 (s, 6H) 3.94-4.08 (m, 2H) 4.46 (d, J=12.36 Hz,2H) 4.60 (d, J=14.20 Hz, 2H) 5.02 (s, 3H) 5.10 (s, 2H) 5.31-5.45 (m, 4H)6.24 (d, J=8.67 Hz, 2H) 6.86-6.94 (m, 2H) 7.07 (t, J=8.51 Hz, 2H) 7.20(s, 1H) 7.26 (s, 1H) 7.34-7.50 (m, 4H) 12.05 (d, J=15.72 Hz, 2H); MS(ESI+) m/z 912.4 (M+H)⁺.

Example 3.27dimethyl({(2R,5R)-1-[3,5-difluoro-4-(4-phenylpiperidin-1-yl)phenyl]pyrrolidine-2,5-diyl}bis{1H-benzimidazole-5,2-diyl(2S)pyrrolidine-2,1-diyl[(1S)-1-(2,3-dihydro-1H-inden-2-yl)-2-oxoethane-2,1-diyl]})biscarbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.51-1.76 (m, 6H) 1.94-2.06 (m, 4H)2.12-2.28 (m, 8H) 2.69-2.89 (m, 12H) 2.92-3.05 (m, 1H) 3.55 (s, 6H)3.77-3.86 (m, 4H) 4.36-4.43 (m, 2H) 5.16-5.24 (m, 2H) 5.35-5.48 (m, 2H)5.97 (d, J=12.90 Hz, 2H) 7.01-7.30 (m, 17H) 7.34 (s, 1H) 7.46 (d, J=8.35Hz, 1H) 7.54-7.60 (m, 2H) 12.07 (s, 1H) 12.18 (s, 1H); MS (ESI+) m/z1175.5 (M+H)⁺.

Example 3.28methyl{(2S)-1-[(2S,3aS,6aS)-2-{5-[(2R,5R)-1-[3,5-difluoro-4-(4-phenylpiperidin-1-yl)phenyl]-5-{2-[(2S,3aS,6aS)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}octahydrocyclopenta[b]pyrrol-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}hexahydrocyclopenta[b]pyrrol-1(2H)-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.72-0.92 (m, 12H) 1.50-1.59 (m, 4H)1.62-1.72 (m, 8H) 1.73-1.81 (m, 2H) 1.83-1.92 (m, 4H) 1.95-2.03 (m, 2H)2.06-2.15 (m, 4H) 2.38-2.46 (m, 2H) 2.75-2.83 (m, 1H) 2.86-3.01 (m, 4H)3.54 (s, 6H) 4.01 (td, J=13.28, 6.83 Hz, 4H) 4.78 (dd, J=7.70, 4.23 Hz,2H) 5.13 (t, J=8.24 Hz, 2H) 5.33-5.45 (m, 2H) 5.92 (dd, J=12.90, 2.82Hz, 2H) 7.07 (d, J=8.67 Hz, 2H) 7.15 (t, J=6.94 Hz, 1H) 7.20-7.29 (m,5H) 7.34 (d, J=4.01 Hz, 1H) 7.39-7.47 (m, 3H) 7.50 (d, J=8.02 Hz, 1H)11.97 (s, 1H) 12.06 (s, 1H); MS (ESI+) m/z 1107.4 (M+H)⁺.

Example 3.29methyl{1-[(2S)-2-{5-[(2R,5R)-1-[3,5-difluoro-4-(4-phenylpiperidin-1-yl)phenyl]-5-{2-[(2S)-1-{3-ethyl-2-[(methoxycarbonyl)amino]pentanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-ethyl-1-oxopentan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.16 (t, J=6.02 Hz, 1H) 0.34 (t, J=6.89Hz, 1H) 0.56-0.99 (m, 10H) 1.16-1.36 (m, 4H) 1.53-1.80 (m, 8H) 1.93-2.09(m, 4H) 2.14-2.30 (m, 4H) 2.80-3.13 (m, 11H) 3.53 (s, 6H) 3.73-3.95 (m,4H) 4.24-4.41 (m, 2H) 5.09-5.20 (m, 2H) 5.30-5.44 (m, 2H) 5.83-5.96 (m,2H) 7.03-7.36 (m, 11H) 7.39-7.62 (m, 2H) 12.00 (s, 1H) 12.13-12.20 (m,1H); MS (ESI+) m/z 1083.5 (M+H)⁺.

Example 3.30dimethyl({(2R,5R)-1-[3,5-difluoro-4-(piperidin-1-yl)phenyl]pyrrolidine-2,5-diyl}bis{1H-benzimidazole-5,2-diyl(2S,3aS,6aS)hexahydrocyclopenta[b]pyrrole-2,1(2H)-diyl[(1S)-1-cyclopentyl-2-oxoethane-2,1-diyl]})biscarbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.17-1.32 (m, 10H) 1.36-1.49 (m, 10H)1.51-1.79 (m, 10 H) 1.87 (dd, J=15.83, 7.26 Hz, 2H) 1.98 (dd, J=13.07,8.40 Hz, 2H) 2.05-2.16 (m, 6H) 2.36-2.46 (m, 4H) 2.72-2.81 (m, 6H) 3.54(s, 6H) 4.11 (q, J=9.40 Hz, 2H) 4.75-4.85 (m, 2H) 5.08-5.18 (m, 2H) 5.36(dt, J=13.66, 6.83 Hz, 2H) 5.88 (ddd, J=12.69, 3.52, 3.42 Hz, 2H) 7.07(d, J=8.35 Hz, 2H) 7.21 (s, 1H) 7.31 (d, J=4.01 Hz, 1H) 7.41 (d, J=8.24Hz, 1H) 7.46-7.56 (m, 3H) 11.88 (d, J=2.49 Hz, 1H) 12.01 (d, J=3.36 Hz,1H); MS (ESI+) m/z 1083.5 (M+H)⁺.

Example 3.31

({(2R,5R)-1-[3,5-difluoro-4-(4-phenylpiperidin-1-yl)phenyl]pyrrolidine-2,5-diyl}bis[1H-benzimidazole-5,2-diyl(2S)pyrrolidine-2,1-diyl])bis[(2S)-tetrahydrofuran-2-ylmethanone]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.36-1.49 (m, J=15.83 Hz, 2H) 1.60-1.75(m, 8H) 1.77-1.91 (m, 6H) 1.94-2.12 (m, 8H) 2.16-2.27 (m, 2H) 2.86-3.08(m, 5H) 3.74 (t, J=6.99 Hz, 6H) 4.57-4.63 (m, 2H) 5.13 (dd, J=9.00, 1.30Hz, 2H) 5.33-5.43 (m, 2H) 5.93 (d, J=13.34 Hz, 2H) 7.06-7.16 (m, 3H)7.20-7.29 (m, 5H) 7.32 (s, 1H) 7.42 (d, J=8.57 Hz, 1H) 7.52 (d, J=8.13Hz, 1H) 12.00 (s, 1H) 12.08 (s, 1H); MS (ESI+) m/z 909.4 (M+H)⁺.

Example 3.32dimethyl({(2R,5R)-1-[3,5-difluoro-4-(piperidin-1-yl)phenyl]pyrrolidine-2,5-diyl}bis{1H-benzimidazole-5,2-diyl(2S,3S,6aS)hexahydrocyclopenta[b]pyrrole-2,1(2H)-diyl[(1S)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethane-2,1-diyl]})biscarbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.10-1.27 (m, 4H) 1.33-1.51 (m, 12H)1.51-1.65 (m, 6H) 1.67-1.80 (m, 4H) 1.83-2.00 (m, 6H) 2.08-2.17 (m, 4H)2.39-2.45 (m, 2H) 2.73-2.85 (m, 8H) 3.03-3.12 (m, 2H) 3.53 (s, 6H)3.70-3.87 (m, 2H) 4.04-4.17 (m, 2H) 4.74-4.83 (m, 2H) 5.08-5.17 (m, 2H)5.31-5.42 (m, 2H) 5.83-5.93 (m, 2H) 7.04-7.11 (m, 2H) 7.21 (d, J=15.83Hz, 2H) 7.41 (d, J=8.02 Hz, 1H) 7.46-7.55 (m, 3H) 11.96 (d, J=4.12 Hz,1H) 12.11 (d, J=4.55 Hz, 1H); MS (ESI+) m/z 1115.4 (M+H)⁺.

Example 3.33methyl{(2S,3R)-1-[(2S,3aS,6aS)-2-{5-[(2R,5R)-1-[3,5-difluoro-4-(piperidin-1-yl)phenyl]-5-(2-{(2S,3aS,6aS)-1-[N-(methoxycarbonyl)-O-methyl-L-threonyl]octahydrocyclopenta[b]pyrrol-2-yl}-1H-benzimidazol-5-yl)pyrrolidin-2-yl]-1H-benzimidazol-2-yl}hexahydrocyclopenta[b]pyrrol-1(2H)-yl]-3-methoxy-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.95 (d, J=6.18 Hz, 3H) 1.03 (d, J=5.75Hz, 3H) 1.35-1.49 (m, 8H) 1.50-1.64 (m, 4H) 1.66-1.81 (m, 6H) 1.84-2.01(m, 6H) 2.07-2.16 (m, 4H) 2.73-2.84 (m, 6H) 3.13 (s, 3H) 3.17 (s, 3H)3.54 (s, 6H) 4.20-4.29 (m, 2H) 4.76-4.84 (m, 2H) 5.12 (t, J=8.19 Hz, 2H)5.37 (dd, J=6.51, 4.88 Hz, 2H) 5.88 (d, J=13.45 Hz, 2H) 7.05 (d, J=8.13Hz, 2H) 7.20 (s, 1H) 7.30 (s, 1H) 7.40 (d, J=7.81 Hz, 1H) 7.47-7.57 (m,3H) 11.98-12.15 (m, 2H); MS (APCI+) m/z 1063.4 (M+H)⁺.

Example 3.34ethyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-[3,5-difluoro-4-(4-phenylpiperidin-1-yl)phenyl]-5-{2-[(2S)-1-{(2S)-2-[(ethoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.75-0.91 (m, 12H) 1.15 (t, J=7.43 Hz,6H) 1.60-1.74 (m, 6H) 1.85-2.07 (m, 8H) 2.16-2.27 (m, 4H) 2.86-3.04 (m,4H) 3.40-3.48 (m, 1H) 3.76-3.85 (m, 4H) 3.98 (q, J=7.08 Hz, 4H) 4.05 (t,J=8.29 Hz, 2H) 5.11-5.19 (m, 2H) 5.34-5.44 (m, 2H) 5.92 (d, J=12.69 Hz,2H) 7.05-7.11 (m, 2H) 7.15 (t, J=6.94 Hz, 1H) 7.20-7.27 (m, 7H) 7.31 (s,1H) 7.42 (d, J=8.24 Hz, 1H) 7.50 (d, J=7.92 Hz, 1H) 12.07 (s, 1H) 12.12(s, 1H); MS (ESI+) m/z 1055.4 (M+H)⁺.

Example 3.35dimethyl({(2R,5R)-1-[3,5-difluoro-4-(piperidin-1-yl)phenyl]pyrrolidine-2,5-diyl)}bis{(6-fluoro-1H-benzimidazole-5,2-diyl)(2S)pyrrolidine-2,1-diyl[(1S)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethane-2,1-diyl]})biscarbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.12-1.33 (m, 4H) 1.38-1.55 (m, 10H)1.66-1.90 (m, 6H) 1.94-2.04 (m, 4H) 2.11-2.24 (m, 2H) 2.75-2.85 (m, 6H)3.01-3.19 (m, 2H) 3.52 (s, 6H) 3.63-3.77 (m, 4H) 3.78-3.89 (m, 6H)4.08-4.18 (m, 2H) 5.07-5.16 (m, 2H) 5.46-5.63 (m, 2H) 5.81-5.93 (m, 2H)6.99-7.12 (m, 2H) 7.31-7.44 (m, 4H) 12.04-12.15 (m, 1H) 12.28-12.35 (m,1H); MS (APCI+) m/z 1071.2 (M+H)⁺.

Example 3.36methyl{(2S,3R)-1-[(2S)-2-{5-[(2R,5R)-1-[3,5-difluoro-4-(piperidin-1-yl)phenyl]-5-(6-fluoro-2-{(2S)-1-[N-(methoxycarbonyl)-O-methyl-L-threonyl]pyrrolidin-2-yl}-1H-benzimidazol-5-yl)pyrrolidin-2-yl]-6-fluoro-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methoxy-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.87-1.11 (m, 8H) 1.35-1.52 (m, 6H)1.71-1.84 (m, 2H) 1.91-2.07 (m, 4H) 2.12-2.26 (m, 4H) 2.79 (s, 4H) 3.08(d, J=37.41 Hz, 6H) 3.41-3.48 (m, 2H) 3.53 (s, 6H) 3.82 (d, J=4.88 Hz,4H) 4.18-4.30 (m, 2H) 5.11 (s, 2H) 5.47-5.63 (m, 2H) 5.81-5.97 (m, 2H)6.99-7.28 (m, 4H) 7.37 (dd, J=25.54, 9.60 Hz, 2H) 12.10 (s, 1H)12.22-12.35 (m, 1 H); MS (ESI+) m/z 1019.4 (M+H)⁺.

Example 3.37methyl{(2S)-1-[(2S,3aS,6aS)-2-{5-[(2R,5R)-1-[3,5-difluoro-4-(piperidin-1-yl)phenyl]-5-{6-fluoro-2-[(2S,3aS,6aS)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}octahydrocyclopenta[b]pyrrol-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-6-fluoro-1H-benzimidazol-2-yl}hexahydrocyclopenta[b]pyrrol-1(2H)-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.80 (dd, J=24.13, 6.45 Hz, 12H)1.36-1.67 (m, 10H) 1.69-1.87 (m, 8H) 1.92-2.17 (m, 6H) 2.37-2.47 (m, 2H)2.78 (s, 6H) 3.53 (s, 6H) 3.92-4.07 (m, 2H) 4.69-4.84 (m, 2H) 5.08 (t,J=8.29 Hz, 2H) 5.36-5.68 (m, 4H) 5.86 (dd, J=11.71, 8.67 Hz, 2H) 7.10(dd, J=31.39, 6.89 Hz, 2H) 7.28-7.51 (m, 4H) 12.02 (s, 1H) 12.21 (d,J=7.27 Hz, 1H); MS (ESI+) m/z 1067.4 (M+H)⁺.

Example 3.38methyl{(2S,3R)-1-[(2S,3aS,6aS)-2-{5-[(2R,5R)-1-[3,5-difluoro-4-(piperidin-1-yl)phenyl]-5-(6-fluoro-2-{(2S,3aS,6aS)-1-[N-(methoxycarbonyl)-O-methyl-L-threonyl]octahydrocyclopenta[b]pyrrol-2-yl}-1H-benzimidazol-5-yl)pyrrolidin-2-yl]-6-fluoro-1H-benzimidazol-2-yl}hexahydrocyclopenta[b]pyrrol-1(2H)-yl]-3-methoxy-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.78-1.07 (m, 8H) 1.36-1.51 (m, 8H)1.51-1.67 (m, 4H) 1.75 (dd, J=12.20, 6.56 Hz, 4H) 1.90 (dd, J=20.22,8.95 Hz, 4H) 2.00-2.14 (m, 4H) 2.37-2.47 (m, 2H) 2.79 (s, 6H) 3.04-3.20(m, 6H) 3.54 (s, 6H) 4.14-4.29 (m, 2H) 4.77 (dd, J=18.00, 7.48 Hz, 2 H)5.07 (t, J=8.24 Hz, 2H) 5.47-5.65 (m, 2H) 5.80-5.94 (m, 2H) 7.08 (dd,J=27.27, 6.78 Hz, 2H) 7.28-7.57 (m, 4H) 12.04 (s, 1H) 12.26 (s, 1H); MS(ESI+) m/z 1099.4 (M+H)⁺.

Example 3.39dimethyl({(2R,5R)-1-[3,5-difluoro-4-(piperidin-1-yl)phenyl]pyrrolidine-2,5-diyl}bis{(6-fluoro-1H-benzimidazole-5,2-diyl)(2S)pyrrolidine-2,1-diyl[(1S)-1-cyclopentyl-2-oxoethane-2,1-diyl]})biscarbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.10-1.29 (m, 6H) 1.34-1.62 (m, 18H)1.71-1.86 (m, 2H) 1.94-2.10 (m, 4H) 2.11-2.24 (m, 4H) 2.74-2.84 (m, 4H)2.94-3.12 (m, 2H) 3.53 (s, 6H) 3.73-3.87 (m, 4H) 4.06-4.17 (m, 2H)5.07-5.18 (m, 2H) 5.47-5.63 (m, 2H) 5.82-5.95 (m, 2H) 7.03 (d, J=6.40Hz, 1H) 7.13 (d, J=7.37 Hz, 1H) 7.30-7.46 (m, 4H) 12.07 (s, 1H) 12.23(s, 1H); MS (APCI+) m/z 1040.3 (M+H)⁺.

Example 3.40dimethyl({(2R,5R)-1-[3,5-difluoro-4-(piperidin-1-yl)phenyl]pyrrolidine-2,5-diyl}bis{(6-fluoro-1H-benzimidazole-5,2-diyl)(2S,3aS,6aS)hexahydrocyclopenta[b]pyrrole-2,1(2H)-diyl[(1S)-1-cyclopentyl-2-oxoethane-2,1-diyl]})biscarbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.12-1.25 (m, 8H) 1.35-1.64 (m, 18H)1.70-1.88 (m, 6H) 1.92-2.15 (m, 8H) 2.36-2.46 (m, 4H) 2.78 (s, 6H) 3.53(s, 6H) 4.07 (dt, J=18.38, 9.24 Hz, 2H) 4.72-4.83 (m, 2H) 5.07 (t,J=8.08 Hz, 2H) 5.46-5.65 (m, 2H) 5.81-5.91 (m, 2H) 7.06 (d, J=6.07 Hz,1H) 7.11-7.19 (m, 1H) 7.34 (dd, J=10.63, 4.88 Hz, 1H) 7.43 (dd, J=11.22,7.21 Hz, 1H) 7.51 (dd, J=13.99, 7.92 Hz, 2H) 11.95 (s, 1H) 12.20 (s,1H); MS (ESI+) m/z 1119.4 (M+H)⁺.

Example 3.41dimethyl({(2R,5R)-1-[3,5-difluoro-4-(piperidin-1-yl)phenyl]pyrrolidine-2,5-diyl}bis{(6-fluoro-1H-benzimidazole-5,2-diyl)(2S,3aS,6aS)hexahydrocyclopenta[b]pyrrole-2,1(2H)-diyl[(1S)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethane-2,1-diyl]})biscarbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.30-1.65 (m, 18H) 1.69-1.94 (m, 12H)2.05-2.15 (m, 4 H) 2.37-2.45 (m, 4H) 2.73-2.87 (m, 6H) 2.97-3.11 (m, 3H)3.53 (s, 6H) 3.77 (dd, J=27.65, 10.08 Hz, 4H) 4.06-4.14 (m, 2H)4.71-4.81 (m, 2H) 5.07 (t, J=8.35 Hz, 2H) 5.43-5.65 (m, 2H) 5.78-5.92(m, 2H) 6.99-7.05 (m, 1H) 7.09 (t, J=6.94 Hz, 1H) 7.33 (dd, J=10.03,6.13 Hz, 1H) 7.50 (dd, J=18.16, 7.86 Hz, 2H) 11.99 (s, 1H) 12.29 (d,J=5.75 Hz, 1H); MS (ESI+) m/z 1151.4 (M+H)⁺.

Example 3.42methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-{3,5-difluoro-4-[4-(4-fluorophenyl)piperidin-1-yl]phenyl}-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.08 (d, J=18.9, 2H), 7.50 (d, J=8.0,1H), 7.41 (d, J=8.3, 1H), 7.33-7.18 (m, 6H), 7.13-7.01 (m, 4H), 5.91 (d,J=13.1, 2H), 5.42-5.33 (m, 2H), 5.19-5.10 (m, 2H), 4.06 (t, J=8.6, 2H),3.86-3.77 (m, 4H), 3.53 (s, 6H), 3.03-2.83 (m, 5H), 2.28-1.54 (m, 18H),0.91-0.73 (m, 12H); MS (ESI+) m/z 1045.4 (M+H)⁺.

Example 3.43methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-(3,5-difluoro-4-{4-[3-(trimethylsilyl)phenyl]piperidin-1-yl}phenyl)-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.31-12.04 (m, 2H), 7.49 (d, J=8.4,1H), 7.40 (d, J=8.2, 1H), 7.34-7.17 (m, 8H), 7.11-7.04 (m, 2H),5.95-5.86 (m, 2H), 5.43-5.31 (m, 2H), 5.18-5.09 (m, 2H), 4.05 (t, J=8.3,2H), 3.86-3.76 (m, 4H), 3.52 (s, 6H), 3.12-2.82 (m, 4H), 2.58-2.52 (m,2H), 2.26-1.83 (m, 11H), 1.72-1.58 (m, 6H), 0.90-0.73 (m, 12H), 0.20 (s,9H); MS (ESI+) m/z 1099.4 (M+H)⁺.

Example 3.44methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-{4-[4-(3,4-difluorophenyl)piperidin-1-yl]-3,5-difluorophenyl}-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.32-12.04 (m, 2H), 7.50 (d, J=8.5,1H), 7.41 (d, J=8.3, 1H), 7.36-7.25 (m, 5H), 7.21 (s, 1H), 7.12-7.05 (m,3H), 5.91 (d, J=12.8, 2H), 5.37 (dd, J=6.0, 2.1, 2H), 5.18-5.11 (m, 2H),4.06 (t, J=8.3, 2H), 3.86-3.79 (m, 4H), 3.53 (s, 6H), 3.12-2.83 (m, 4H),2.27-2.10 (m, 4H), 2.08-1.49 (m, 15H), 0.93-0.67 (m, 12H); MS (ESI+) m/z1063.3 (M+H)⁺.

Example 3.45methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-{4-[4-(3,5-difluorophenyl)piperidin-1-yl]-3,5-difluorophenyl}-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.47-11.91 (m, 2H), 7.52-7.40 (m, 2H),7.36-7.19 (m, 4H), 7.10 (d, J=7.9, 2H), 7.04-6.92 (m, 3H), 5.92 (d,J=12.7, 2H), 5.46-5.32 (m, 2H), 5.20-5.10 (m, 2H), 4.06 (t, J=8.3, 2H),3.89-3.75 (m, 4H), 3.53 (s, 6H), 3.13-2.82 (m, 4H), 2.63-2.54 (m, 3H),2.28-2.12 (m, 4H), 2.08-1.84 (m, 6H), 1.77-1.56 (m, 6H), 0.91-0.71 (m,12H); MS (ESI+) m/z 1063.4 (M+H)⁺.

Example 3.46methyl{(2S)-1-[(2S)-2-(6-fluoro-5-{(2R,5S)-5-{6-fluoro-2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}-1-[2-(4-phenylpiperidin-1-yl)pyrimidin-5-yl]pyrrolidin-2-yl}-1H-benzimidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO) δ=12.42-12.16 (m, 2H), 7.81-7.55 (m, 4H),7.45-7.12 (m, 9H), 5.23-5.06 (m, 2H), 5.02-4.86 (m, 2H), 4.57-4.45 (m,2H), 4.13-3.96 (m, 2H), 3.92-3.70 (m, 4H), 3.53 (s, 6H), 2.75 (t,J=12.8, 2H), 2.62-2.54 (m, J=8.1, 2H), 2.28-1.59 (m, 15H), 1.53-1.36 (m,2H), 0.98-0.66 (m, 12H). MS (ESI; M+H) m/z=1029.4.

Example 3.47methyl{(2S)-1-[(2S)-2-(6-fluoro-5-{(2R,5S)-5-{6-fluoro-2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}-1-[2-(piperidin-1-yl)pyrimidin-5-yl]pyrrolidin-2-yl}-1H-benzimidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO) δ 12.41-12.15 (m, 2H), 7.79-7.54 (m, 4H),7.45-7.24 (m, 4H), 5.20-5.06 (m, 2H), 5.01-4.85 (m, 2H), 4.12-4.01 (m,2H), 3.88-3.73 (m, 4H), 3.52 (s, 6H), 3.50-3.42 (m, 4H), 2.55 (s, 2H),2.27-1.77 (m, 12H), 1.51 (s, 2H), 1.38 (s, 4H), 0.93-0.73 (m, 12H). MS(ESI; M+H) m/z=953.4.

Example 3.48methyl{(2S,3R)-1-[(2S)-2-{5-[(2R,5R)-1-{4-[4-(2,6-difluorophenyl)piperazin-1-yl]-3,5-difluorophenyl}-5-(6-fluoro-2-{(2S)-1-[N-(methoxycarbonyl)-O-methyl-L-threonyl]pyrrolidin-2-yl}-1H-benzimidazol-5-yl)pyrrolidin-2-yl]-6-fluoro-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methoxy-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO) δ 12.31-12.08 (m, 2H), 7.41 (dd, J=11.2, 6.3,1H), 7.34 (dd, J=10.4, 4.7, 1H), 7.24 (d, J=8.3, 1H), 7.18-6.97 (m, 6H),5.90 (dd, J=22.3, 9.7, 2H), 5.57 (s, 2H), 5.16-5.06 (m, 2H), 4.25 (dd,J=15.5, 8.2, 2H), 3.87-3.76 (m, 3H), 3.53 (s, 6H), 3.50-3.40 (m, 2H),3.25 (d, J=3.5, 1H), 3.13 (d, J=1.1, 3H), 3.09 (s, 4H), 3.04 (d, J=2.6,3H), 2.96 (s, 4H), 2.55-2.47 (m, 2H), 2.26-1.71 (m, 10H), 1.08-0.89 (m,6H). MS (ESI; M+H) m/z=1132.4.

Example 3.49methyl{(2S,3R)-1-[(2S)-2-{5-[(2S,5S)-1-{4-[4-(2,6-difluorophenyl)piperazin-1-yl]-3,5-difluorophenyl}-5-(6-fluoro-2-{(2S)-1-[N-(methoxycarbonyl)-O-methyl-L-threonyl]pyrrolidin-2-yl}-1H-benzimidazol-5-yl)pyrrolidin-2-yl]-6-fluoro-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methoxy-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO) δ 12.33-12.04 (m, 2H), 7.41 (dd, J=11.3, 4.7,1H), 7.36 (dd, J=10.5, 3.0, 1H), 7.28 (d, J=7.9, 1H), 7.21 (d, J=8.1,1H), 7.16 (t, J=7.8, 1H), 7.10-6.96 (m, 4H), 5.92 (q, J=10.7, 2H),5.69-5.49 (m, 2H), 5.12 (dd, J=7.6, 4.1, 2H), 4.27 (t, J=7.6, 2H), 3.82(s, 3H), 3.53 (d, J=3.1, 6H), 3.47 (d, J=6.3, 2H), 3.24 (d, J=2.3, 1H),3.19 (s, 3H), 3.13 (s, 3H), 3.09 (s, 4H), 2.96 (s, 4H), 2.46 (s, 2H),2.28-1.71 (m, 10H), 1.09-1.00 (m, 6H). MS (ESI; M+H) m/z=1132.4.

Example 3.50methyl{(2S)-1-[(2S)-2-{5-[(2S,5S)-1-{4-[4-(2,6-difluorophenyl)piperazin-1-yl]-3,5-difluorophenyl}-5-{6-fluoro-2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-6-fluoro-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO) δ 12.47-11.97 (m, 2H), 7.44-7.26 (m, 4H),7.19-6.96 (m, 5H), 5.93 (q, J=12.0, 2H), 5.67-5.48 (m, 2H), 5.18-5.07(m, 2H), 4.05 (dd, J=14.8, 8.3, 2H), 3.87-3.71 (m, 4H), 3.53 (d, J=3.1,6H), 3.09 (s, 4H), 2.96 (s, 4H), 2.46 (s, 2H), 2.25-1.70 (m, 12H),0.89-0.76 (m, 12H). MS (ESL M+H) m/z=1100.4.

Example 3.51dimethyl([(2R,5R)-1-{4-[4-(2,6-difluorophenyl)piperazin-1-yl]-3,5-difluorophenyl}pyrrolidine-2,5-diyl]bis{(6-fluoro-1H-benzimidazole-5,2-diyl)(2S)pyrrolidine-2,1-diyl[(1S)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethane-2,1-diyl]})biscarbamate

¹H NMR (400 MHz, DMSO) δ 12.37-12.08 (m, 2H), 7.44-7.30 (m, 4H),7.12-6.95 (m, 5H), 5.90 (q, J=11.6, 2H), 5.66-5.47 (m, 2H), 5.16-5.05(m, 2H), 4.17-4.04 (m, 2H), 3.88-3.61 (m, 7H), 3.52 (d, J=3.1, 6H),3.23-2.80 (m, 13H), 2.26-1.67 (m, 12H), 1.55-1.05 (m, 10H). MS (ESI;M+H) m/z=1184.4

Example 3.52methyl{(2S,3R)-1-[(2S)-2-{5-[(2R,5R)-1-{3,5-difluoro-4-[4-(4-fluorophenyl)piperidin-1-yl]phenyl}-5-(6-fluoro-2-{(2S)-1-[N-(methoxycarbonyl)-O-methyl-L-threonyl]pyrrolidin-2-yl}-1H-benzimidazol-5-yl)pyrrolidin-2-yl]-6-fluoro-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methoxy-1-oxobutan-2-yl}carbamate

Example 3.53

dimethyl([(2R,5R)-1-{3,5-difluoro-4-[4-(4-fluorophenyl)piperidin-1-yl]phenyl}pyrrolidine-2,5-diyl]bis{(6-fluoro-1H-benzimidazole-5,2-diyl)(2S)pyrrolidine-2,1-diyl[(1S)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethane-2,1-diyl]})biscarbamate2H NMR (400 MHz, DMSO) δ 12.36-12.07 (m, 2H), 7.44-7.22 (m, 6H),7.12-6.99 (m, 4H), 5.88 (dd, J=23.6, 11.2, 2H), 5.64-5.47 (m, 2H),5.15-5.06 (m, 2H), 4.17-4.06 (m, 2H), 3.89-3.61 (m, 7H), 3.52 (d, J=3.3,6H), 3.25-2.82 (m, 9H), 2.26-2.08 (m, 4H), 2.05-1.92 (m, 4H), 1.91-1.57(m, 9H), 1.54-1.38 (m, 4H), 1.38-1.02 (m, 6H). MS (ESI; M+H) m/z=1165.5.

The following Example compounds 4.1-4.62 can be made from theappropriate listed intermediate following the methods of GeneralProcedures 12/12B.

Intermediate amines:

-   (S)-6,6′-((2R,5R)-1-(4-(cyclopentyloxy)-3-fluorophenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(3-methyl-4-(piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-((3aR,7aS)-1H-isoindol-2(3H,3aH,4H,5H,6H,7H,7aH)-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(3,5-dichloro-4-(piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(2,5-difluoro-4-(piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(4-((2R,6S)-2,6-dimethylpiperidin-1-yl)-3,5-difluorophenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(2,3,5-trifluoro-4-(piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(4-cyclohexyl-3-fluorophenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(3,4-difluorophenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(4-ethoxyphenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(4-(2,2-difluoroethoxy)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(4-(3,5-dimethylpiperidin-1-yl)-3,5-difluorophenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   6,6′-{(2R,5R)-1-[4-(pentafluoro-λ⁶-sulfanyl)phenyl]pyrrolidine-2,5-diyl}bis{2-[(2S)-pyrrolidin-2-yl]-1H-benzimidazole}    (ACD Name v12);-   (S)-6,6′-((2S,5S)-1-(4-cyclopropylphenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2S,5S)-1-(4-cyclopropyl-3,5-difluorophenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   1-(1-(4-((2R,5R)-2,5-bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)pyrrolidin-1-yl)-2,6-difluorophenyl)-4-phenylpiperidin-4-yl)ethanone;-   (S,S,S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((2S,3aS,6aS)-octahydrocyclopenta[b]pyrrol-2-yl)-1H-benzo[d]imidazole);-   (S,S,S)-6,6′-((2R,5R)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(2-42S,3aS,6aS)-octahydrocyclopenta[b]pyrrol-2-yl)-1H-benzo[d]imidazole);-   2-(4-((2R,5R)-2,5-bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)pyrrolidin-1-yl)-2,6-difluorophenyl)-2-azabicyclo[2.2.2]octane;-   (S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(4-isopropylpiperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(4-(4,4-dimethylpiperidin-1-yl)-3,5-difluorophenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(4-(3,3-dimethylazetidin-1-yl)-3,5-difluorophenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(4-(4-phenylpiperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(4-(3-phenylpropyl)piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(4-(4-tert-butylpiperidin-1-yl)-3,5-difluorophenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(4-(naphthalen-2-yl)piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(4-(2,3-dihydrospiro[indene-1,4′-piperidine]-1′-yl)-3,5-difluorophenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(3-phenylpiperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(3-phenylpyrrolidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(4-(4-methoxyphenyl)piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(4-fluoro-4-phenylpiperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(4-(4-fluoro-4-phenylpiperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-(2R,5R)-1-(3,5-difluoro-4-(4-(fluorodiphenylmethyl)piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(4-phenylpiperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(4-(benzyloxy)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   6-((2R,5R)-1-(3,5-difluoro-4-(piperidin-1-yl)phenyl)-5-(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)pyrrolidin-2-yl)-5-fluoro-2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole;-   (S)-6,6′-((2R,5R)-1-(4-(4-benzylpiperidin-1-yl)-3,5-difluorophenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(4-(4-benzylpiperidin-1-yl)-3,5-difluorophenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2S,5R)-1-(3,5-difluoro-4-(4-phenylpiperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   4-(4-((2R,5R)-2,5-bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)pyrrolidin-1-yl)-2,6-difluorophenyl)-2-phenylmorpholine;-   (S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(2-phenylpiperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (2S,6R)-4-(4-((2R,5R)-2,5-bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)pyrrolidin-1-yl)-2,6-difluorophenyl)-2,6-dimethylmorpholine;-   (S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(3-azaspiro[5.5]undecan-3-yl)phenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(4-(4-cyclohexylpiperidin-1-yl)-3,5-difluorophenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-4-(4-((2R,5R)-2,5-bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)pyrrolidin-1-yl)-2,6-difluorophenyl)-2-phenylmorpholine;-   (S)-6,6′-((2S,5R)-1-(3,5-difluoro-4-(piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(4-phenylpiperazin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S,R)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(242S,4R)-4-fluoropyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(4-(pyrimidin-2-yl)piperazin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(4-(4-(2,4-difluorophenyl)piperidin-1-yl)-3,5-difluorophenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);-   (S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(4-(4-fluorophenyl)piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole).-   (S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(4-(5-methylthiophen-2-yl)piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole);    and-   (S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(4-fluoro-4-phenylpiperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole).

Intermediate Acids:

-   (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid;-   (S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic    acid;-   (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid;-   (S)-2-cyclopropyl-2-(methoxycarbonylamino)acetic acid;-   (2S,3R)-3-tert-butoxy-2-(methoxycarbonylamino)butanoic acid;-   (S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic    acid;-   (S)-2-cyclopentyl-2-(methoxycarbonylamino)acetic acid; and-   (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid.

Example 4.1methyl{(2S)-1-[(2S)-2-{6-[(2R,5R)-1-[4-(cyclopentyloxy)-3-fluorophenyl]-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-6-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.74-0.89 (m, 12H), 1.37-1.77 (m, 12H),1.81-2.06 (m, 6 H), 2.11-2.29 (m, 4H), 3.54 (s, 6H), 3.72-3.92 (m, 4H),3.95-4.16 (m, 2H), 4.40-4.52 (m, 1H), 5.07-5.23 (m, 2H), 5.26-5.44 (m,2H), 5.96-6.17 (m, 2H), 6.63-6.98 (m, 2H), 7.00-7.16 (m, 2 H), 7.16-7.35(m, 4H), 7.35-7.54 (m, J=31.23 Hz, 2H), 11.93-12.32 (m, 2H); MS (EST)m/z=934.5 (M+H)⁺.

Example 4.2methyl{(2S)-1-[(2S)-2-(5-{(2R,5R)-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}-1-[3-methyl-4-(piperidin-1-yl)phenyl]pyrrolidin-2-yl}-1H-benzimidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.74-0.89 (m; 12H) 1.35-1.41 (m, 2H)1.44-1.52 (m, 4H) 1.62-1.67 (m, 2H) 1.86-1.93 (m, 5H) 1.94-2.03 (m, 4H)2.15-2.24 (m, 4H) 2.48-2.54 (m, 6H) 3.52 (s, 6H) 3.74-3.84 (m, 4H)4.00-4.09 (m, 2H) 5.06-5.18 (m, 2H) 5.28-5.37 (m, 2H) 6.07-6.12 (m, 1H)6.17-6.21 (m, 1H) 6.56-6.62 (m, 1H) 6.99-7.30 (m, 6H) 7.35 (d, J=8.24Hz, 1H) 7.44 (d, J=8.24 Hz, 1H) 11.94-12.04 (m, 2H); MS (EST+) m/z 929.5(M+H)⁺.

Example 4.3methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-{3,5-difluoro-4-[(3aR,7aS)-octahydro-2H-isoindol-2-yl]phenyl}-5-{2-[(2S)-1-[(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.71-0.94 (m, 12H) 1.22-1.31 (m, 2H)1.35-1.53 (m, 6H) 1.66-1.74 (m, 2H) 1.86-2.24 (m, 12H) 2.90-2.97 (m, 2H)3.05-3.15 (m, 2H) 3.36-3.42 (m, 2 H) 3.54 (s, 6H) 3.77-3.86 (m, 4H) 4.06(t, J=8.29 Hz, 2H) 5.09-5.20 (m, 2H) 5.29-5.40 (m, 2H) 5.89 (d, J=12.25Hz, 2H) 7.03-7.13 (m, 2H) 7.18-7.33 (m, 4H) 7.40 (d, J=8.13 Hz, 1H) 7.48(d, J=8.24 Hz, 1H) 11.95-12.25 (m, 2H); MS (ESI+) m/z 991.5 (M+H)⁺.

Example 4.4methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-[3,5-dichloro-4-(piperidin-1-yl)phenyl]-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.68-0.94 (m, 12H) 1.36-2.28 (m, 20H)2.84 (s, 4H) 3.54 (s, 6H) 3.82 (s, 4H) 4.04-4.09 (m, 2H) 5.09-5.19 (m,2H) 5.33-5.50 (m, 2H) 6.30 (t, J=2.49 Hz, 2H) 6.99-7.57 (m, 8H) 12.04(s, 1H) 12.09 (s, 1H); MS (ESI+) m/z 983 (M+H)⁺.

Example 4.5methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-[2,5-difluoro-4-(piperidin-1-yl)phenyl]-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.80 (s, 12H) 1.08-2.71 (m, 24H) 3.53(s, 6H) 3.81 (s, 4H) 3.97-4.11 (m, 2H) 5.13 (s, 2H) 5.51 (s, 2H)6.34-6.70 (m, 2H) 7.00-7.60 (m, 8H) 11.87-12.30 (m, 2H); MS (ESI+) m/z952 (M+H)⁺.

Example 4.6methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-{4-[(2R,6S)-2,6-dimethylpiperidin-1-yl]-3,5-difluorophenyl}-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.58 (s, 6H) 0.73-0.92 (m, 12H)1.08-2.37 (m, 20H) 3.53 (s, 6H) 3.82 (s, 4H) 4.06 (q, J=7.92 Hz, 2H)5.15 (s, 2H) 5.39 (s, 2H) 5.88 (d, J=13.01 Hz, 2H) 7.02-7.58 (m, 10H)12.01 (s, 1H) 12.18 (s, 1H); MS (ESI+) m/z 979 (M+H)⁺.

Example 4.7 methyl{(2S)-1-[(2S)-2-(5-{(2R,5R)-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}-1-[2,3,5-trifluoro-4-(piperidin-1-yl)phenyl]pyrrolidin-2-yl}-1H-benzimidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.72-0.93 (m, 12H) 1.34-2.38 (m, 20H)2.77 (s, 4H) 3.53 (s, 6H) 3.82 (s, 4H) 4.00-4.13 (m, 2H) 5.14 (s, 2H)5.56 (s, 2H) 6.27-6.47 (m, 1H) 6.97-7.49 (m, 8H) 12.01 (s, 1H) 12.08 (d,J=1.84 Hz, 1H); MS (ESI+) m/z 970 (M+H)⁺.

Example 4.8methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-(4-cyclohexyl-3-fluorophenyl)-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-6-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, CDCl₃) δ ppm 10.48 (m, 1H), 10.32 (s, 1H), 7.70 (d,J=8.0 Hz, 1H), 7.53 (s, H), 7.34 (d, J=8.1 Hz, 1H), 7.13 (d, J=5.5 Hz,3H), 6.72 (s, 1H), 6.03 (m, 2H), 5.40 (m, 5H), 5.26 (d, J=1.7 Hz, 3H),4.34 (dd, J=8.7, 7.0 Hz, 2H), 3.84 (d, J=7.6 Hz, 2H), 3.70 (s, 6H), 3.62(m, 3H), 3.09 (m, 2H), 2.57 (m, 4H), 2.33 (m, 2H), 2.17 (m, 5H), 1.97(m, 3H), 1.73 (m, 8H), 1.17 (m, 8H), 0.89 (t, J=6.4, 12 H); MS (ESI+)m/z (rel abundance) 933 (100, M+H), 934 (53).

Example 4.9methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-(3,4-difluorophenyl)-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-6-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, CDCl₃) δ ppm 10.49 (d, J=9.0 Hz, 1H), 10.38 (s, 1H),7.70 (d, J=8.1 Hz, 1H), 7.51 (s, 1H), 7.35 (d, J=8.3 Hz, 1H), 7.12 (dd,J=10.9, 6.3 Hz, 3H), 6.69 (dd, J=9.4, 5.7 Hz, 1H), 6.13 (d, J=7.2 Hz,1H), 6.00 (s, 1H), 5.41 (m, 4H), 5.27 (m, 2H), 4.34 (m, 2H), 4.06 (d,J=6.6 Hz, 1H), 3.85 (m, 2H), 3.73 (s, 6H), 3.64 (m, 2H), 3.08 (m, 2H),2.61 (m, 2H), 2.34 (m, 2H), 2.19 (m, 4H), 1.96 (m, 2H), 1.79 (m, 2H),1.64 (m, 4H), 0.92 (m, 12H); MS (ESI+) m/z (rel abundance) 868 (100,M+H), 869 (43).

Example 4.10methyl{(2S)-1-[(2S)-2-{6-[(2R,5R)-1-(4-ethoxyphenyl)-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-6-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.92-0.75 (m, 12H), 1.21-1.10 (m, 3H),1.33-1.21 (m, 1H), 1.76-1.64 (m, 2H), 2.06-1.85 (m, 7H), 2.28-2.08 (m,4H), 3.54 (s, 6H), 3.73 (q, J=7.0, 2H), 3.81 (s, 4H), 4.11-3.99 (m, 2H),5.18-5.06 (m, 2H), 5.33 (s, 2H), 6.24 (d, J=8.9, 2H), 6.51 (dt, J=4.9,9.4, 2H), 7.04 (t, J=7.7, 2H), 7.34-7.18 (m, 4H), 7.36 (d, J=8.2, 1H),7.44 (d, J=8.2, 1H), 12.02 (s, 2H); MS (ESI) m/z 876 (M+H)⁺, 874 (M−H)⁻.

Example 4.11methyl{(2S)-1-[(2S)-2-{6-[(2R,5R)-1-[4-(2,2-difluoroethoxy)phenyl]-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-6-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, methanol-d₄) δ ppm 0.85 (dd, J=6.7, 20.0, 12H),1.88-1.75 (m, 2H), 2.06-1.95 (m, 3H), 2.22-2.06 (m, 3H), 2.34-2.23 (m,2H), 2.49-2.34 (m, 2H), 2.71-2.56 (m, 2H), 3.64 (s, 6H), 4.13-3.76 (m,6H), 4.22 (dd, J=5.4, 10.3, 1H), 5.28-5.17 (m, 2H), 5.37 (t, J=6.4, 2H),5.96 (tt, J=3.9, 55.2, 1H), 6.31 (t, J=9.7, 2H), 6.60-6.51 (m, 2H), 6.98(d, J=8.4, 1H), 7.23 (d, J=8.3, 2H), 7.35 (d, J=17.8, 2H), 7.50 (d,J=8.3, 2H); MS (ESI) m/z 912 (M+H)⁺, 910 (M−H)⁻.

Example 4.12methyl{(2S)-1-[(2S)-2-{6-[(2R,5R)-1-[4-(3,5-dimethylpiperidin-1-yl)-3,5-difluorophenyl]-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-6-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.50 (q, J=11.9, 1H), 0.97-0.64 (m,18H), 1.32-1.20 (m, 2H), 1.81-1.46 (m, 5H), 2.09-1.80 (m, 6H), 2.32-2.13(m, 5H), 2.75 (dd, J=10.0, 40.2, 2H), 3.18-3.05 (m, 1H), 3.54 (s, 6H),3.82 (s, 4H), 4.14-3.95 (m, 2H), 5.14 (s, 2H), 5.36 (d, J=7.2, 2H), 5.88(d, J=12.8, 2H), 7.14-7.02 (m, 2H), 7.19 (s, 1H), 7.33-7.23 (m, 3H),7.41 (d, J=8.2, 1H), 7.49 (d, J=8.2, 1H), 12.37-11.98 (m, 2H); MS (ESI)m/z 979 (M+H)⁺.

Example 4.13methyl{(2S)-1-[(2S)-2-(6-{(2R,5R)-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-6-yl}-1-[4-(pentafluoro-lambda˜-6˜-sulfanyl)phenyl]pyrrolidin-2-yl}-1H-benzimidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.92-0.69 (m, 12H), 2.08-1.61 (m, 8H),2.20 (s, 4H), 3.53 (s, 6H), 3.82 (s, 4H), 4.05 (t, J=8.0, 2H), 5.13 (dt,J=4.9, 9.8, 2H), 5.49 (dd, J=10.8, 15.8, 2H), 6.37 (d, J=8.6, 2H),7.13-6.81 (m, 3H), 7.20 (d, J=8.8, 1H), 7.28 (dd, J=4.6, 9.9, 3H),7.45-7.34 (m, 4H), 7.48 (d, J=8.2, 1H), 12.16 (dd, J=22.6, 68.2, 2H); MS(ESI) m/z 958 (M+H)⁺, 956 (M−H)⁻.

Example 4.14methyl{(2S,3R)-1-[(2S)-2-{5-[(2S,5S)-1-(4-cyclopropylphenyl)-5-(2-{(2S)-1-[N-(methoxycarbonyl)-O-methyl-L-threonyl]pyrrolidin-2-yl}-1H-benzimidazol-5-yl)pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methoxy-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.37 (m, 2H) 0.68, (s, 2H) 1.08 (d, 6H)1.54-1.64 (m, 2H) 1.69 (s, 2H) 1.99 (s, 4H) 2.17 (s, 7H) 3.18 (s, 6H)3.42-3.53 (m, 2H) 3.54 (s, J=1.41 Hz, 6H) 3.84 (s, 3H) 4.28 (s, 2H) 5.12(s, 2H) 5.34 (s, 2H) 6.22 (s, 2H) 6.61 (s, 2H) 7.05 (s, 2H) 7.16 (s, 2H)7.36 (s, 2H) 11.97 (s, 1H), 12.08 (s, 1H); MS (ESI+) m/z 904.5 (M+H)⁺,(ESI−) m/z 902.3 (M−H)⁻.

Example 4.15methyl{(2S)-1-[(2S)-2-{6-[(2R,5R)-1-(4-cyclopropyl-3,5-difluorophenyl)-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-6-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, CDCl₃) δ ppm 10.47 (br s, 1H) 10.30-10.41 (br s, 1H)7.69 (br s, 1H) 7.49 (s, 1H) 7.30-7.43 (br s, 1H) 7.04-7.20 (m, 3H)5.75-5.89 (m, 2H) 5.37 (m, 4H) 5.23 (s, 2H) 4.34 (t, 2H) 3.83 (m, 2H)3.71 (s, 6H) 3.56-3.67 (m, 2H) 3.11 (m, 2H) 2.58 (br s, 2H) 2.33 (m, 2H)2.08-2.27 (m, 4H) 2.01 (m, 2H) 1.78 (br s, 2H) 0.82-0.96 (m, 12H) 0.71(m, 4H).

Example 4.16dimethyl([(2R,5R)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis{1H-benzimidazole-6,2-diyl(2S)pyrrolidine-2,1-diyl[(1S)-1-cyclopropyl-2-oxoethane-2,1-diyl]})biscarbamate

¹H NMR (500MHz, DMSO-d₉₆) δ ppm 0.48-0.24 (m, 7H), 0.89-0.81 (m, 1H),1.01 (s, 3H), 1.07 (s, 6H), 1.14 (dd, J=8.7, 16.6, 1H), 1.32-1.17 (m,4H), 1.75-1.64 (m, 1H), 2.05-1.78 (m, 4H), 2.24-2.09 (m, 3H), 2.45-2.39(m, 2H), 3.21-3.12 (m, 1H), 3.53 (s, 6H), 3.72-3.63 (m, 2H), 3.76 (s,2H), 4.03-3.85 (m, 2H), 5.17-5.04 (m, 1H), 5.44-5.26 (m, 2H), 6.26 (d,J=8.8, 1H), 6.95-6.81 (m, 2H), 7.06-6.95 (m, 1H), 7.09 (t, J=8.3, 1H),7.20 (d, J=4.3, 1H), 7.35-7.25 (m, 1H), 7.55-7.36 (m, 4H), 12.28-11.84(m, 2H); MS (ESI+) m/z 884 (M+H)⁺, (ESI−) m/z 882 (M−H)⁻.

Example 4.17methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-[4-(4-acetyl-4-phenylpiperidin-1-yl)-3,5-difluorophenyl]-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.75-0.91 (m, 12H) 1.68 (d, J=4.66 Hz,2H) 1.83 (s, 3H) 1.87-2.38 (m, 16H) 2.78-2.90 (m, 4H) 3.54 (s, 6H) 3.82(s, 4H) 4.06 (t, J=8.35 Hz, 2H) 5.09-5.18 (m, 2H) 5.27-5.41 (m, 2H) 5.88(d, J=12.90 Hz, 2H) 7.02-7.51 (m, 13H) 12.07 (d, J=16.91 Hz, 2H); MS(ESI+) m/z 1070 (M+H)⁺.

Example 4.18methyl{(2S)-1-[(2S,3aS,6aS)-2-{5-[(2R,5R)-1-[3,5-difluoro-4-(piperidin-1-yl)phenyl]-5-{2-[(3aS,6aS)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}octahydrocyclopenta[b]pyrrol-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}hexahydrocyclopenta[b]pyrrol-1(2H)-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.64-0.96 (m, 13H) 1.31-2.18 (m, 21H)3.50-3.57 (m, 6 H) 3.93-4.07 (m, 2H) 4.72-4.85 (m, 1H) 5.13 (t, 1H) 5.37(s, 2H) 5.90 (dd, 2H) 7.06 (d, 2H) 7.21 (s, 1H) 7.33 (d, 1H) 7.36-7.56(m, J=8.13 Hz, 4H) 11.96 (s, 1H) 12.03-12.08 (m, 1H) 12.24 (none, 1H);MS (ESI+) m/z 1031.5 (M+H)⁺, (ESI−) m/z 1029.4 (M−H)⁻.

Example 4.19methyl{(2S)-1-[(2S,3aS,6aS)-2-{5-[(2R,5R)-1-(4-tert-butylphenyl)-5-{2-[(3aS,6aS)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}octahydrocyclopenta[b]pyrrol-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}hexahydrocyclopenta[b]pyrrol-1(2H)-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.62-0.93 (m, 13H) 1.42-2.16 (m, 25H)2.78 (s, 1H) 3.54 (s, 6H) 4.01 (s, 2H) 4.77 (s, 1H) 5.11 (t, J=8.08 Hz,2H) 5.35 (s, 2H) 6.26 (d, J=8.67 Hz, 2H) 6.83-6.97 (m, 2H) 7.05 (s, 2H)7.21 (s, 1H) 7.27-7.32 (m, 1H) 7.34-7.55 (m, 4H) 11.92 (s, 1H) 12.01 (s,1H); MS (ESI+) m/z 968.5 (M+H)⁺, (ESI−) m/z 966.4 (M−H)⁻, 1011.7(M+COOH—H)⁻.

Example 4.20methyl[(2S)-1-(2-{5-[(2R,5R)-1-(4-tert-butylphenyl)-5-{2-[(2S)-pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl]carbamate

The title compound can be prepared by reacting the amine with oneequivalent of an acid instead of two. ¹H NMR (400 MHz, DMSO-d₆) δ ppm0.67-0.90 (m, 6H) 0.97-1.17 (m, 9H) 1.53-2.46 (m, 13H) 3.26-3.42 (m,J=11.39 Hz, 2H) 3.54 (s, 3H) 3.85 (d, J=4.34 Hz, 2H) 4.07-4.13 (m, 1H)4.88-4.98 (m, 1H) 5.15-5.23 (m, 1H) 5.45 (d, J=7.16 Hz, 1H) 5.50 (d,J=6.94 Hz, 1H) 6.26 (d, J=8.78 Hz, 2H) 6.92 (d, J=8.78 Hz, 2H) 7.19-7.77(m, 7H) 9.15 (s, 1H) 9.66 (s, 1H); MS (ESI+) m/z 731 (M+H)⁺.

Example 4.21methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-[4-(2-azabicyclo[2.2.2]oct-2-yl)-3,5-difluorophenyl]-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.74-1.02 (m, 12H), 1.41-2.27 (m, 26H),2.65 (s, 1H), 3.05-3.26 (m, 3H), 3.54 (s, 6H), 4.06 (t, J=8.35 Hz, 2H),5.07-5.20 (m, 2H), 5.26-5.45 (m, 2H), 5.89 (d, J=12.36 Hz, 2H),7.00-7.14 (m, 2H), 7.16-7.33 (m, 4H), 7.44 (dd, J=32.42, 8.24 Hz, 2 H),12.06 (two s, 2H); MS (ESI+) m/z 977 (M+H)⁺, (ESI−) m/z 975 (M−H)⁻.

Example 4.22methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-{3,5-difluoro-4-[4-(propan-2-yl)piperidin-1-yl]phenyl}-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.74-0.91 (m, 18H), 0.91-1.05 (m, 1H),1.07-1.21 (m, 3 H), 1.31-1.43 (m, 1H), 1.51 (d, J=11.17 Hz, 2H),1.63-1.77 (m, 2H), 1.84-2.26 (m, 11H), 2.72-2.88 (m, 4H), 3.54 (s, 6H)3.82 (br s, 4H), 4.06 (t, J=8.35 Hz, 2H), 5.07-5.23 (m, 2H), 5.29-5.45(m, 2H), 5.88 (d, J=12.79 Hz, 2H), 7.02-7.12 (m, 2H), 7.16-7.32 (m, 4H),7.41 (d, J=8.13 Hz, 1H), 7.49 (d, J=8.13 Hz, 1H), 12.07 (two s, 2H); MS(ESI+) m/z 994 (M+H)⁺.

Example 4.23dimethyl({(2R,5R)-1-[4-(4,4-dimethylpiperidin-1-yl)-3,5-difluorophenyl]pyrrolidine-2,5-diyl}bis{1H-benzimidazole-5,2-diyl(2S)pyrrolidine-2,1-diyl[(1S)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethane-2,1-diyl]})biscarbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.87 (s, 6H), 1.18-1.34 (m, 9H),1.34-1.59 (m, 4H), 1.61-1.93 (m, 5H), 1.93-2.06 (m, 4H), 2.09-2.27 (m,4H), 2.77 (s, 4H), 2.90-3.27 (m, 4H), 3.53 (s, 6 H), 3.62 (d, J=11.71Hz, 1H), 3.67-3.89 (m, 7H), 4.14 (q, J=8.10 Hz, 2H), 5.08-5.20 (m, 2H),5.30-5.43 (m, 2H), 5.81-5.94 (m, 2H), 7.03-7.52 (m, 8H), 12.10 (two s,2H); MS (ESI+) m/z 1063 (M+H)⁺, (ESI−) m/z 1061 (M−H)⁻.

Example 4.24methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-[4-(3,3-dimethylazetidin-1-yl)-3,5-difluorophenyl]-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.76-0.94 (m, 12H), 1.13 (s, 6H),1.61-1.74 (m, 2H), 1.81-2.28 (m, 9H), 3.07-3.18 (m, 1H), 3.49 (s, 4H),3.54 (s, 6H), 3.82 (br s, 4H), 4.07 (t, J=8.24 Hz, 2 H), 5.14 (t, J=7.54Hz, 2H), 5.25-5.40 (m, 2H), 5.79-5.94 (m, 2H), 7.01-7.07 (m, 2H),7.08-7.34 (m, 4H), 7.39 (d, J=8.13 Hz, 1H), 7.47 (d, J=8.24 Hz, 1H),12.05 (two s, 2H); MS (ESI+) m/z 951 (M+H)⁺.

Example 4.25methyl{(2S)-1-[(2S)-2-(5-{(2R,5R)-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}-1-[4-(4-phenylpiperidin-1-yl)phenyl]pyrrolidin-2-yl}-1H-benzimidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.74-0.93 (m, 12H), 1.61-1.79 (m, 6H),1.84-2.09 (m, 6 H), 2.11-2.27 (m, 4H), 2.40-2.60 (m, 4H), 3.35 (s, 3H),3.53 (s, 6H), 3.82 (s, 4H), 4.06 (t, J=8.29 Hz, 2H), 5.08-5.19 (m, 2H),5.28-5.46 (m, 2H), 6.26 (d, J=8.67 Hz, 2H), 6.55-6.67 (m, 2H), 7.06 (t,J=7.32 Hz, 2H), 7.13-7.32 (m, 9H), 7.37 (d, J=8.24 Hz, 1H), 7.45 (d,J=8.24 Hz, 1H), 12.02 (s, 2H); MS (ESI+) m/z 991 (M+H)⁺, (ESI−) m/z 989(M−H)⁻.

Example 4.26methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-{3,5-difluoro-4-[4-(3-phenylpropyl)piperidin-1-yl]phenyl}-5-{6-fluoro-2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-6-fluoro-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.68-0.84 (m, 12H), 0.98-1.30 (m, 8H),1.47-1.60 (m, 5 H), 1.63-2.07 (m, 9H), 2.09-2.24 (m, 3H), 2.78 (s, 4H),3.51 (s, 6H), 3.71-3.87 (m, 4H), 3.97-4.12 (m, 2H), 5.03-5.17 (m, 2H),5.43-5.63 (m, 2H), 5.78-5.96 (m, 2H), 7.02 (dd, J=6.78, 2.33 Hz, 1H),7.08-7.19 (m, 4H), 7.19-7.35 (m, 5H), 7.39 (dd, J=11.28, 6.29 Hz, 1H),11.50-12.73 (m, 2H); MS (ESI+) m/z 1105 (M+H)⁺; MS (ESI−)m/z 1103(M−H)⁻.

Example 4.27methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-[4-(4-tert-butylpiperidin-1-yl)-3,5-difluorophenyl]-5-{6-fluoro-2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-6-fluoro-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.69-0.76 (m, 4H), 0.76-0.91 (m, 17H),1.13-1.27 (m, 3 H), 1.55 (d, J=11.39 Hz, 2H), 1.67-2.09 (m, 9H),2.11-2.26 (m, 4H), 2.72-2.94 (m, 4H), 3.50-3.57 (m, 6H), 3.62-3.86 (m,5H), 3.99-4.11 (m, 2H), 5.03-5.17 (m, 2H), 5.46-5.63 (m, 2H), 5.87 (dd,J=12.52, 7.21 Hz, 2H), 7.03 (d, J=6.40 Hz, 1H), 7.13 (d, J=6.94 Hz, 1H),7.25-7.37 (m, 3 H), 7.40 (dd, J=11.17, 6.29 Hz, 1H), 11.67-12.63 (m,2H); MS (ESI+) m/z 1043 (M+H)⁺; MS (ESI−) m/z 1041 (M−H)⁻.

Example 4.28dimethyl({(2R,5R)-1-[4-(4-tert-butylpiperidin-1-yl)-3,5-difluorophenyl]pyrrolidine-2,5-diyl}bis{(6-fluoro-1H-benzimidazole-5,2-diyl)(2S)pyrrolidine-2,1-diyl[(1S)-1-cyclopentyl-2-oxoethane-2,1-diyl]})biscarbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.80 (s, 9H), 1.08-1.63 (m, 24H),1.65-1.87 (m, 3H), 1.92-2.25 (m, 10H), 2.37-2.45 (m, 1H), 2.73-2.93 (m,4H), 3.60-3.91 (m, 4H), 4.13 (t, J=8.24 Hz, 2 H), 5.11 (d, J=6.83 Hz,2H), 5.45-5.63 (m, 2H), 5.80-5.97 (m, 2H), 6.95-7.08 (m, 1H), 7.13 (d,J=6.61 Hz, 1H), 7.34 (dd, J=10.25, 3.74 Hz, 1H), 7.37-7.46 (m, 3H),11.73-12.50 (m, 2H); MS (ESI+) m/z 1095 (M+H)⁺; MS (ESI−) m/z 1093(M−H)⁻.

Example 4.29methyl{(2S,3R)-3-tert-butoxy-1-[(2S)-2-{5-{(2R,5R)-5-{2-[(2S)-1-{(2S,3R)-3-tert-butoxy-2-[(methoxycarbonyl)amino]butanoyl}pyrrolidin-2-yl]-6-fluoro-1H-benzimidazol-5-yl}-1-[4-(4-tert-butylpiperidin-1-yl)-3,5-difluorophenyl]pyrrolidin-2-yl}-6-fluoro-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.82 (d, J=14.64 Hz, 13H), 0.88-0.96 (m,4H), 1.02 (s, 7H), 1.12 (d, J=33.83 Hz, 11H), 1.49-2.31 (m, 9H),2.69-2.93 (m, 4H), 3.27 (s, 1H), 3.50-3.57 (m, 6 H), 3.64-3.94 (m, 9H),4.03-4.31 (m, 3H), 5.06-5.23 (m, 1H), 5.38-5.69 (m, 2H), 5.78-5.95 (m,2H), 6.46-6.63 (m, 1H), 6.70-6.87 (m, 1H), 6.92-7.04 (m, 1H), 7.08-7.29(m, 1H), 7.34 (dd, J=10.63, 1.84 Hz, 1H), 7.38-7.55 (m, 1H), 11.40-12.88(m, 2H); MS (ESI+) m/z 1159 (M+H)⁺.

Example 4.30methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-{3,5-difluoro-4-[4-(2-naphthyl)piperidin-1-yl]phenyl}-5-{6-fluoro-2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-6-fluoro-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.73 (d, J=6.51 Hz, 4H), 0.76-0.85 (m,8H), 1.19-1.32 (m, 2H), 1.69-2.08 (m, 12H), 2.11-2.25 (m, 3H), 2.67-2.78(m, 1H), 2.92-3.18 (m, 5H), 3.52 (d, J=1.19 Hz, 6H), 3.72-3.87 (m, 4H),3.99-4.11 (m, 2H), 5.06-5.19 (m, 2H), 5.49-5.67 (m, 2H), 5.83-6.00 (m,2H), 7.01-7.09 (m, 1H), 7.16 (d, J=7.05 Hz, 1H), 7.25-7.37 (m, 3H),7.38-7.53 (m, 4H), 7.68-7.93 (m, 4H), 11.88-12.65 (m, 2H); MS (ESI+) m/z1113 (M+H)⁺; MS (ESI−) m/z 1111 (M−H)⁻.

Example 4.31methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-[4-(2,3-dihydro-1′H-spiro[indene-1,4′-piperidin]-1′-yl)-3,5-difluorophenyl]-5-{6-fluoro-2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-6-fluoro-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, CDCl₃) δ ppm 10.53-10.63 (m, 1H) 10.31-10.41 (m, 1H)7.43-7.52 (m, 1H) 7.30-7.40 (m, 1H) 7.10-7.25 (m, 5H) 6.92-7.00 (m, 1H)5.86 (d, 2H) 5.23-5.51 (m, 61-1) 4.26-4.40 (m, 2H) 3.77-3.91 (m, 2H)3.68-3.72 (m, 6H) 3.56-3.66 (m, 2H) 2.83-3.26 (m, 8H) 1.81-2.61 (m, 16H)0.71-1.10 (m, 12H); MS (ESI) m/z 1089 (M+H)⁺.

Example 4.32methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-[3,5-difluoro-4-(3-phenylpiperidin-1-yl)phenyl]-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-6-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.07 (s, 1H), 12.01 (s, 1H), 7.48 (d,J=8.3 Hz, 1H), 7.38 (m, 2H), 7.20 (s, 8H), 7.09 (m, 2H), 5.90 (d, J=12.9Hz, 2H), 5.36 (d, J=7.5 Hz, 2H), 5.14 (s, 2 H), 4.05 (t, J=8.1 Hz, 2H),3.81 (s, 4H), 3.54 (s, 6H), 2.85 (s, 4H), 2.18 (s, 5H), 1.94 (m, 7H),1.61 (m, 5H), 0.77 (m, 12H); MS (ESI+) m/z (rel abundance) 1027 (100,M+H)⁺.

Example 4.33methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-[3,5-difluoro-4-(3-phenylpyrrolidin-1-yl)phenyl]-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-6-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.09 (d, J=14.8 Hz, 2H), 7.47 (m, 2H),7.45 (m, 2H), 7.24 (m, 8H), 7.08 (s, 2H), 5.93 (d, J=12.1 Hz, 2H), 5.38(s, 2H), 5.15 (s, 2H), 4.06 (t, J=8.4 Hz, 2H), 3.82 (s, 4H), 3.53 (s,6H), 3.13 (m, 4H), 2.19 (s, 4H), 1.90 (m, 6H), 1.70 (s, 2H), 0.80 (m,12H); MS (ESI+) m/z (rel abundance) 1013 (100, M+H)⁺, 1014 (58).

Example 4.34methyl{(2S)-1-[(2S)-2-{6-[(2R,5R)-1-{3,5-difluoro-4-[4-(4-methoxyphenyl)piperidin-1-yl]phenyl}-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-6-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.97-0.69 (m, 12H), 1.24 (s, 1H),1.78-1.50 (m, 6H), 2.10-1.85 (m, 7H), 2.19 (s, 4H), 2.47-2.38 (m, 1H),3.03-2.80 (m, 4H), 3.53 (s, 6H), 3.69 (s, 3H), 3.82 (s, 4H), 4.17-3.93(m, 2H), 5.22-5.08 (m, 2H), 5.45-5.29 (m, 2H), 5.91 (d, J=12.8, 2H),6.81 (d, J=8.7, 2H), 7.17-7.02 (m, 4H), 7.21 (s, 1H), 7.34-7.26 (m, 3H),7.41 (d, J=8.2, 1H), 7.50 (d, J=8.2, 1H), 12.17 (dd, J=19.9, 74.7, 2H);MS (ESI) m/z 1057 (M+H)⁺, 1055 (M−H)⁺.

Example 4.35methyl{(2S)-1-[(2S)-2-{6-[(2R,5R)-1-[3,5-difluoro-4-(4-fluoro-4-phenylpiperidin-1-yl)phenyl]-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-6-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.91-0.75 (m, 12H), 2.11-1.60 (m, 12H),2.28-2.12 (m, 4H), 2.55 (d, J=5.5, 2H), 2.84-2.71 (m, 2H), 3.28-3.06 (m,2H), 3.53 (s, 6H), 3.83 (s, 4H), 4.11-3.99 (m, 2H), 5.19-5.09 (m, 2H),5.45-5.30 (m, 2H), 5.94 (d, J=12.8, 2H), 7.13-7.05 (m, 2H), 7.45-7.18(m, 10H), 7.50 (d, J=8.3, 1H), 12.11 (d, J=15.2, 2H); MS (ESI) m/z 1045(M+H)⁺, 1043 (M−H)⁴.

Example 4.36methyl{(2S)-1-[(2S)-2-{6-[(2R,5R)-1-[4-(4-fluoro-4-phenylpiperidin-1-yl)phenyl]-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-6-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.92-0.74 (m, 12H), 1.23 (d, J=3.9, 1H),1.69 (d, J=3.6, 2H), 2.09-1.80 (m, 9H), 2.26-2.09 (m, 5H), 2.81-2.69 (m,2H), 3.26-3.10 (m, 3H), 3.53 (s, 6H), 3.89-3.74 (m, 4H), 4.05 (t, J=8.4,2H), 5.18-5.06 (m, 2H), 5.34 (d, J=4.5, 2H), 6.27 (d, J=8.7, 2H), 6.65(dt, J=4.2, 8.6, 2H), 7.06 (t, J=7.8, 2H), 7.21 (s, 1H), 7.43-7.26 (m,9H), 7.45 (d, J=8.2, 1H), 12.04 (s, 2H); MS (ESI) m/z 1009 (M+H)⁺, 1007(M−H)⁺.

Example 4.37methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-(3,5-difluoro-4-{4-[fluoro(diphenyl)methyl]piperidin-1-yl}phenyl)-5-{6-fluoro-2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-6-fluoro-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, methanol-d₄) δ ppm 0.99-0.69 (m, 12H), 1.42-1.26 (m,3H), 1.55 (dd, J=12.0, 24.4, 2H), 2.42-1.85 (m, 12H), 2.62-2.43 (m, 3H),3.01-2.74 (m, 4H), 3.63 (s, 6H), 3.90-3.77 (m, 2H), 4.05-3.90 (m, 2H),4.20 (d, J=7.4, 1H), 5.24-5.08 (m, 2H), 5.52 (t, J=5.8, 2H), 5.92-5.72(m, 2H), 7.07 (s, 1H), 7.18 (t, J=7.3, 2H), 7.29 (t, J=7.5, 6H), 7.33(s, 1H), 7.43 (d, J=7.3, 4H); MS (EST) m/z 1171 (M+H)⁺.

Example 4.38methyl{(2S,3R)-1-[(2S)-2-{5-[(2R,5R)-1-[3,5-difluoro-4-(4-phenylpiperidin-1-yl)phenyl]-5-(6-fluoro-2-{(2S)-1-[N-(methoxycarbonyl)-O-methyl-L-threonyl]pyrrolidin-2-yl}-1H-benzimidazol-5-yl)pyrrolidin-2-yl]-6-fluoro-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methoxy-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.92 (d, J=5.5, 2H), 1.04 (dd, J=5.8,12.0, 4H), 1.68 (s, 4H), 1.80 (s, 2H), 2.09-1.91 (m, 4H), 2.27-2.10 (m,4H), 3.01-2.82 (m, 3H), 3.03 (s, 4H), 3.13 (s, 4H), 3.25 (s, 2H), 3.44(dd, J=6.5, 12.8, 3H), 3.53 (s, 6H), 3.81 (s, 3H), 4.31-4.14 (m, 2H),5.17-5.02 (m, 2H), 5.66-5.41 (m, 2H), 5.97-5.80 (m, 2H), 7.13-6.99 (m,2H), 7.19-7.13 (m, 2H), 7.31-7.19 (m, 5H), 7.38 (dd, J=9.8, 26.3, 2H),12.39-12.01 (m, 2H); MS (ESI) m/z 1095 (M+H)⁺, 1093 (M−H)⁺.

Example 4.39dimethyl({(2R,5R)-1-[3,5-difluoro-4-(4-phenylpiperidin-1-yl)phenyl]pyrrolidine-2,5-diyl}bis{(6-fluoro-1H-benzimidazole-5,2-diyl)(2S)pyrrolidine-2,1-diyl[(1S)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethane-2,1-diyl]})biscarbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.37-1.07 (m, 6H), 1.56-1.36 (m, 4H),1.73-1.60 (m, 4H), 1.78 (s, 4H), 2.06-1.93 (m, 4H), 2.26-2.06 (m, 4H),3.26-2.81 (m, 8H), 3.52 (s, 6H), 3.91-3.60 (m, 8H), 4.12 (dd, J=6.9,15.8, 2H), 5.11 (s, 2H), 5.54 (d, J=10.0, 2H), 5.99-5.81 (m, 2H), 7.05(dd, J=6.3, 23.5, 2H), 7.16 (t, J=6.9, 1H), 7.31-7.20 (m, 5H), 7.45-7.30(m, 4H), 12.23 (d, J=83.3, 2H); MS (ESI) m/z 1147 (M+H)⁺.

Example 4.40dimethyl({(2R,5R)-1-[3,5-difluoro-4-(4-phenylpiperidin-1-yl)phenyl]pyrrolidine-2,5-diyl}bis{(6-fluoro-1H-benzimidazole-5,2-diyl)(2S)pyrrolidine-2,1-diyl[(1S)-1-cyclopentyl-2-oxoethane-2,1-diyl]})biscarbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.61-1.10 (m, 18H), 1.67 (s, 4H),1.90-1.72 (m, 2H), 2.13-1.93 (m, 6H), 2.18 (s, 4H), 3.08-2.86 (m, 4H),3.17 (d, J=5.1, 1H), 3.52 (s, 6H), 3.89-3.70 (m, 4H), 4.20-4.01 (m, 2H),5.11 (s, 2H), 5.56 (d, J=21.5, 2H), 5.96-5.83 (m, 2H), 7.04 (d, J=6.7,1H), 7.16 (t, J=7.0, 2H), 7.31-7.20 (m, 4H), 7.39 (dt, J=8.1, 25.5, 4H),12.16 (d, J=61.1, 2H); MS (ESI) m/z 1115 (M+H)⁺, 1113 (M−H)⁺.

Example 4.41methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-[4-(benzyloxy)phenyl]-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.02 (s, 2H), 7.28 (m, 13H), 6.60 (m,2H), 6.23 (m, 2H), 5.33 (m, 2H), 5.14 (m, 2H), 4.90 (m, 2H), 3.81 (m,4H), 3.56 (s, 6H), 2.20 (m, 6H), 1.98 (m, 6H), 1.70 (m, 2H), 0.86 (m,12H); MS (ESI) m/z 938 (M+H)⁺.

Example 4.42methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-(3,5-difluoro-4-{4-[4-(trifluoromethyl)phenyl]piperazin-1-yl}phenyl)-5-{6-fluoro-2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-6-fluoro-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.55 (m, 2H), 7.48 (d, J=8.8 Hz, 2H),7.34 (m, 2H), 7.18 (m, 2H), 7.04 (d, J=7.8 Hz, 2H), 5.99 (m, 2H), 5.63(m, 2H), 5.13 (m, 2H), 4.06 (m, 2H), 3.80 (m, 2H), 3.53 (s, 6H), 3.25(m, 8H), 2.99 (m, 4H), 2.05 (m, 12H), 0.81 (m, 12H); MS (ESI) m/z 1132(M+H)⁺.

Example 4.43methyl{(2S)-1-[(2S)-2-{6-[(2R,5R)-1-[3,5-difluoro-4-(piperidin-1-yl)phenyl]-5-{5-fluoro-2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-6-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.68-0.89 (m, 12H) 1.34-1.50 (m, 6H)1.65-2.06 (m, 9H) 2.12-2.24 (m, 4H) 2.70-2.82 (m, 4H) 3.52 (d, J=2.49Hz, 6H) 3.73-3.86 (m, 4H) 3.99-4.08 (m, 2H) 5.06-5.19 (m, 2H) 5.26-5.43(m, 1H) 5.46-5.56 (m, 1H) 5.86 (d, J=12.04 Hz, 2H) 6.98 (d, J=6.51 Hz,1H) 7.02-7.11 (m, 1H) 7.21 (d, J=6.94 Hz, 1H) 7.26-7.35 (m, 2H) 7.39 (d,J=8.35 Hz, 1H) 7.45-7.51 (m, 1H) 12.01-12.26 (m, 2H); MS (ESI+) m/z 969(M+H)⁺.

Example 4.44methyl{(2S)-1-[(2S)-2-{6-[(2R,5R)-1-[4-(4-benzylpiperidin-1-yl)-3,5-difluorophenyl]-5-{5-fluoro-2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-6-yl}pyrrolidin-2-yl]-5-fluoro-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.67-0.88 (m, 12H) 1.22 (s, 12H)1.42-1.51 (m, 5H) 1.73-2.04 (m, 12H) 2.12-2.21 (m, 4H) 2.72-2.81 (m, 5H)3.48-3.54 (m, 6H) 3.72-3.83 (m, 3H) 3.97-4.06 (m, 2H) 5.05-5.13 (m, 2H)5.46-5.58 (m, 2H) 5.79-5.89 (m, 2H) 6.99-7.04 (m, 1H) 7.09-7.16 (m, 5H)7.20-7.34 (m, 6H) 7.35-7.42 (m, 1H) 7.51-7.64 (m, 3H) 12.10 (s, 1H)12.23 (s, 1 H); MS (ESI+) m/z 1077 (M+H)⁺.

Example 4.45dimethyl([(2R,5R)-1-(3,5-difluoro-4-{4-[4-(trifluoromethyl)phenyl]piperazin-1-yl}phenyl)pyrrolidine-2,5-diyl]bis{(5-fluoro-1H-benzimidazole-6,2-diyl)(2S)pyrrolidine-2,1-diyl[(1S)-1-cyclopentyl-2-oxoethane-2,1-diyl]})biscarbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.09-1.64 (m, 18H) 1.71-1.86 (m, 2H)1.92-2.23 (m, 10

H) 2.91-3.03 (m, 5H) 3.22-3.30 (m, 4H) 3.52 (s, 6H) 3.71-3.87 (m, 4H)4.12 (t, J=8.40 Hz, 2H) 5.05-5.16 (m, 2H) 5.48-5.65 (m, 2H) 5.85-5.99(m, 2H) 7.03 (d, J=8.89 Hz, 3H) 7.14 (d, J=6.29 Hz, 1H) 7.30-7.38 (m,1H) 7.40 (d, J=9.54 Hz, 2H) 7.46 (d, J=8.67 Hz, 2H) 12.08 (s, 1H) 12.20(s, 1H); MS (ESI+) m/z 1184 (M+H)⁺.

Example 4.46dimethyl([(2R,5R)-1-(3,5-difluoro-4-{4-[4-(trifluoromethyl)phenyl]piperazin-1-yl}phenyl)pyrrolidine-2,5-diyl]bis{(5-fluoro-1H-benzimidazole-6,2-diyl)(2S)pyrrolidine-2,1-diyl[(1S)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethane-2,1-diyl]})biscarbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.09-1.33 (m, 4H) 1.38-1.54 (m, 4H)1.70-1.88 (m, 4H) 1.92-2.05 (m, 4H) 2.10-2.25 (m, 3H) 2.95-3.03 (m, 4H)3.03-3.20 (m, 3H) 3.21-3.29 (m, 4H) 3.51 (s, 6H) 3.62-3.89 (m, 6H)4.05-4.17 (m, 2H) 5.06-5.15 (m, 2H) 5.48-5.64 (m, 2H) 5.83-5.98 (m, 2H)7.03 (d, J=8.67 Hz, 3H) 7.07 (d, J=6.29 Hz, 1H) 7.29-7.42 (m, 3H) 7.46(d, J=8.78 Hz, 2H) 12.11 (s, 1H) 12.32 (s, 1H); MS (ESI+) m/z 1216(M+H)⁺.

Example 4.47methyl{(2S)-1-[(2S)-2-{6-[(2R,5R)-1-[4-(4-benzylpiperidin-1-yl)-3,5-difluorophenyl]-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-6-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.07 (d, J=19.1, 2H), 7.48 (d, J=8.3,2H), 7.40 (d, J=8.1, 2H), 7.34-7.10 (m, 8H), 7.07 (s, 2H), 5.87 (d,J=12.3, 2H), 5.35 (s, 2H), 5.14 (s, 1H), 3.78 (d, J=28.9, 2H), 3.54 (s,6H), 2.76 (s, 3H), 2.19 (s, 4H), 2.07-1.80 (m, 6H), 1.68 (s, 2H), 1.46(d, J=10.4, 3H), 1.25-1.08 (m, 2H), 0.92-0.71 (m, 12H); MS (ESI+) m/z1041.4 (M+H)⁺, (ESI−) m/z 1039.3 (M−H)⁻.

Example 4.48methyl{(2S)-1-[(2S)-2-{5-[(2S,5R)-1-[3,5-difluoro-4-(4-phenylpiperidin-1-yl)phenyl]-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.76-0.94 (m, 12H), 1.60-2.30 (m, 14H),2.88-3.09 (m, 4 H), 3.54 (s, 6H), 3.84 (s, 3H), 4.02-4.15 (m, J=8.1, 8.1Hz, 2H), 4.77-4.97 (m, 2H), 5.17 (d, J=2.9 Hz, 2H), 5.95-6.10 (m, 2H),7.08-7.70 (m, 13H), 12.09-12.23 (m, 2H).

Example 4.49methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-[3,5-difluoro-4-(2-phenylmorpholine-4-yl)phenyl]-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.69-0.92 (m, 12H), 1.69 (d, J=5.1 Hz,2H), 1.82-2.30 (m, 12H), 2.70-3.16 (m, J=63.6 Hz, 6H), 3.54 (s, 6H),3.81 (s, 3H), 3.99-4.12 (m, 2H), 4.47 (dd, J=9.1, 3.7 Hz, 1H), 5.08-5.19(m, 2H), 5.29-5.48 (m, 2H), 5.92 (d, J=13.4 Hz, 2H), 7.07 (t, J=7.9 Hz,2H), 7.16-7.35 (m, J=0.8 Hz, 10H), 7.40 (d, J=8.1 Hz, 1H), 7.49 (d,J=8.3 Hz, 1H), 12.06 (s, 1 H), 12.11 (s, 1H); MS (APCI+) m/z 1030.1(M+H).

Example 4.50methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-[3,5-difluoro-4-(2-phenylpiperidin-1-yl)phenyl]-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.81-1.01 (m, 12H), 1.24-2.35 (m, 22H),3.60 (s, 6H), 3.89 (s, 4H), 3.94-4.20 (m, 3H), 5.22 (s, 2H), 5.30 (d,J=4.3 Hz, 2H), 5.73 (dd, J=13.1, 3.6 Hz, 2 H), 6.92-7.44 (m, 13H), 7.48(d, J=8.1 Hz, 1H), 12.08 (s, 1H), 12.17 (s, 1H); MS (APCI+) m/z 1028.2(M+H)⁺.

Example 4.51methyl[(2S)-1-{(2S)-2-[5-(1-{4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-3,5-difluorophenyl}-5-{6-fluoro-2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl)-6-fluoro-1H-benzimidazol-2-yl]pyrrolidin-1-yl}-3-methyl-1-oxobutan-2-yl]carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.67-0.90 (m, 12H), 0.96 (s, 6H),1.01-1.31 (m, 2H), 1.68-2.25 (m, 12H), 3.51 (s, 6H), 3.78 (s, 3H), 4.01(q, J=7.2 Hz, 2H), 5.10 (d, J=4.8 Hz, 2H), 5.43-5.65 (m, 2H), 5.79-5.97(m, 2H), 7.02 (d, J=5.3 Hz, 1H), 7.11 (d, J=6.8 Hz, 1H), 7.21-7.46 (m, 4

H), 12.11 (s, 1H), 12.24 (s, 1H); MS (ESI) m/z 1017.4 (M+H)⁺.

Example 4.52methyl{(2S)-1-[(2S)-2-{5-[(2S,5R)-1-[3,5-difluoro-4-(piperidin-1-yl)phenyl]-5-{6-fluoro-2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-6-fluoro-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.72-0.94 (m, j=10.5, 10.5 Hz, 12H),1.36-1.58 (m, 6H), 1.77-2.28 (m, 14H), 2.83 (s, 4H), 3.53 (s, 6H), 3.82(s, 4H), 3.97-4.14 (m, 2H), 4.92-5.07 (m, 2

H), 5.09-5.20 (m, 2H), 5.83-6.02 (m, 2H), 7.21-7.79 (m, 6H), 12.14-12.44(m, 2H); MS (APCI+) m/z 987.8 (M+H)⁺.

Example 4.53methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-[4-(3-azaspiro[5.5]undec-3-yl)-3,5-difluorophenyl]-5-{6-fluoro-2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-6-fluoro-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.64-0.94 (m, 12H), 1.21-1.44 (m, 16H),1.68-2.25 (m, J=78.0 Hz, 12H), 2.78 (s, 4H), 3.53 (s, 6H), 3.80 (s, 4H),4.04 (t, J=7.1 Hz, 2H), 5.11 (s, 2H), 5.55 (dd, J=19.8, 4.2 Hz, 2H),5.79-5.99 (m, 2H), 7.03 (d, J=6.0 Hz, 1H), 7.13 (d, J=6.5 Hz, 1H),7.24-7.48 (m, 4H), 12.12 (s, 1H), 12.24 (s, 1H); MS (ESI) m/z 1055.4(M+H)⁺.

Example 4.54methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-[4-(4-cyclohexylpiperidin-1-yl)-3,5-difluorophenyl]-5-{6-fluoro-2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-6-fluoro-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.65-0.97 (m, 12H), 0.98-1.33 (m, 10H),1.50-2.25 (m, 20H), 2.72-2.91 (m, 4H), 3.53 (s, 6H), 3.79 (s, 4H), 4.04(t, J=8.1 Hz, 2H), 5.11 (s, 2H), 5.54 (dd, J=14.7, 6.7 Hz, 2H),5.79-5.97 (m, 2H), 7.03 (d, J=6.7 Hz, 1H), 7.13 (d, J=6.9 Hz, 1H),7.24-7.46 (m, 4H), 12.11 (s, 1H), 12.23 (s, 1H); MS (ESI+) m/z 1069.5(M+H)⁺.

Example 4.55methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-{3,5-difluoro-4-[(2S)-2-phenylmorpholine-4-yl]phenyl}-5-{6-fluoro-2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-6-fluoro-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.60-0.95 (m, 12H), 1.64-2.08 (m, 10H),2.09-2.25 (m, 4 H), 2.70-3.18 (m, 4H), 3.53 (s, 6H), 3.64-3.86 (m, 4H),3.91 (d, J=11.4 Hz, 1H), 4.03 (t, J=8.2 Hz, 2H), 4.48 (d, J=7.5 Hz, 1H),5.10 (s, 2H), 5.43-5.69 (m, 2H), 5.80-6.03 (m, 2H), 7.03 (d, J=6.8 Hz,1H), 7.14 (d, J=6.7 Hz, 1H), 7.20-7.45 (m, 10H), 12.10 (s, 1H), 12.24(s, 1H); MS (ESI+) m/z 1065.4 (M+H)⁺.

Example 4.56methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-{4-[4-(2,4-difluorophenyl)piperidin-1-yl]-3,5-difluorophenyl}-5-{6-fluoro-2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-6-fluoro-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.68-0.92 (m, 14H), 1.58-2.08 (m, 11H),2.09-2.27 (m, 4 H), 2.71-3.14 (m, 6H), 3.52 (s, 6H), 3.68-3.89 (m, 4H),3.98-4.10 (m, 2H), 5.05-5.17 (m, 2H), 5.48-5.68 (m, 2H), 5.83-5.99 (m,2H), 6.95-7.08 (m, 2H), 7.09-7.21 (m, 2H), 7.25-7.46 (m, 5 H),12.06-12.39 (m, 2H); MS (ESI+) m/z 1099.3 (M+H)⁺.

Example 4.57methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-{3,5-difluoro-4-[4-(4-fluorophenyl)piperidin-1-yl]phenyl}-5-{6-fluoro-2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-6-fluoro-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d_(b)) δ ppm 0.67-0.93 (m, 14H), 1.53-2.09 (m,11H), 2.10-2.25 (m, 4H), 2.83-3.15 (m, 6H), 3.53 (s, 6H), 3.69-3.88 (m,4H), 3.98-4.10 (m, 2H), 5.05-5.17 (m, 2H), 5.48-5.67 (m, 2H), 5.83-5.99(m, 2H), 6.99-7.20 (m, 4H), 7.22-7.47 (m, 6H), 12.02-12.47 (m, 2H); MS(ESI+) m/z 1081.4 (M+H)⁺.

Example 4.58methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-[3,5-difluoro-4-(4-phenylpiperazin-1-yl)phenyl]-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.72-0.95 (m, 12H) 1.69 (s, 1H)1.84-2.11 (m, 2H) 2.20 (s, 4H) 2.97 (s, 4H) 3.09 (s, 4H) 3.54 (s, 6H)3.82 (s, 4H) 4.03 (q, J=7.05 Hz, 6H) 5.15 (s, 2H) 5.39 (s, 2H) 5.95 (s,2H) 6.75 (s, 2H) 6.90 (d, J=8.24 Hz, 2H) 7.08 (t, 2H) 7.17 (t, J=7.92Hz, 2H) 7.30 (s, 2H) 7.48 (s, 2H) 7.66 (s, 2H) 7.92 (s, 2H) 12.09 (s,2H); MS (ESI+) m/z 1028.4, (ESI−) m/z 1026.4 (M−H)⁻.

Example 4.59methyl{(2S)-1-[(2S,4R)-2-{5-[(2R,5R)-1-[3,5-difluoro-4-(piperidin-1-yl)phenyl]-5-{2-[(2S,4R)-4-fluoro-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}-4-fluoropyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.76 (m, 16H) 0.89 (m, 3H) 1.45 (m, 5H)1.70 (m, 2H) 1.85 (m, 1H) 2.76 (d, 2H) 3.17 (d, J=5.10 Hz, 2H) 3.53 (s,6H) 3.87-4.13 (m, 4H) 4.31 (m, 1H) 5.17 (d, 2H) 5.36 (m, 3H) 5.57 (s,1H) 5.89 (d, 2H) 7.09 (m, 2H) 7.18-7.25 (m, 1H) 7.29 (m, 3H) 7.48 (m,3H) 12.22 (s, 2H); MS (ESI+) m/z 987.4, (ESI−) m/z 985.2 (M−H)⁻.

Example 4.60methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-{3,5-difluoro-4-[4-(pyrimidin-2-yl)piperazin-1-yl]phenyl}-5-{6-fluoro-2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-6-fluoro-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.67-0.93 (m, 12H) 1.99 (m, 16H) 2.18(m, 4H) 2.87 (m, 4 H) 3.53 (s, 6H) 3.56 m, 2H) 3.74 (m, 10H) 5.11 (m,2H) 5.53 (m, 2H) 5.90 (m, 2H) 6.60 (t, J=4.72 Hz, 1H) 7.04 (m, 2H) 7.32(m, 4H) 8.33 (d, J=4.77 Hz, 2H) 12.14 (s, 1H) 12.22 (s, 1H); MS (ESI+)m/z 1066.4, (ESI−) m/z 1064.1 (M−H)⁻.

Example 4.61methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-{3,5-difluoro-4-[4-(5-methyl-2-thienyl)piperidin-1-yl]phenyl}-5-{6-fluoro-2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-6-fluoro-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-D6) δ ppm 0.71-0.98 (m, 12H), 1.49-2.31 (m, 18H),2.42 (s, 3H), 2.87-3.11 (m, J=14.1 Hz, 5H), 3.59 (s, 6H), 3.77-3.94 (m,J=9.1 Hz, 4H), 4.05-4.17 (m, 2H), 5.08-5.26 (m, 2H), 5.53-5.74 (m, 2H),5.89-6.05 (m, 2H), 6.64 (d, J=2.4 Hz, 1H), 6.68 (d, J=3.5 Hz, 1H),7.04-7.14 (m, 1H), 7.16-7.25 (m, 1H), 7.31-7.53 (m, 4H), 12.09-12.23 (m,1H), 12.26-12.41 (m, 1H); MS (ESI) m/z 1083.3 (M+H).

Example 4.62methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-[3,5-difluoro-4-(4-fluoro-4-phenylpiperidin-1-yl)phenyl]-5-{6-fluoro-2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-6-fluoro-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO) δ 0.84-0.69 (m, 12H), 0.90-0.84 (m, 2H),1.93-1.76 (m, 7H), 2.00 (dd, J=6.8, 14.5, 8H), 2.23-2.12 (m, 5H), 3.52(s, 6H), 3.87-3.73 (m, 4H), 4.08-3.97 (m, 2H), 5.16-5.06 (m, 2H),5.65-5.48 (m, 2H), 5.99-5.86 (m, 2H), 7.06 (d, J=6.7, 1H), 7.15 (d,J=6.9, 1H), 7.31 (d, J=7.0, 3H), 7.36 (d, J=7.7, 2H), 7.41 (t, J=7.6,4H), 12.19 (d, J=44.3, 2H). MS (ESI) m/z 1081 (M+H)⁺.

Example 5.1methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-[3,5-difluoro-4-(4-phenylpiperidin-1-yl)phenyl]-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

In a 250 mL round-bottomed flask cooled in an ice bath was added(S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(4-phenylpiperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole)(2.57 mmol), (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (0.945g, 5.40 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol hydrate (0.984 g, 6.43mmol) in DMF (25 mL) to give an orange solution. 4-Methylmorpholine(2.83 mL, 25.7 mmol) andN¹—((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochloride (1.232 g, 6.43 mmol) were added, and the mixture wasstirred at ambient temperature for 2 hours and then diluted into EtOAc.The EtOAc layer was washed with aqueous saturated NaHCO₃, H₂O, andsaturated NaCl. The organic layer was treated with 3-mercaptopropylsilica for 1 hour, dried (Na₂SO₄), filtered and concentrated to a yellowfoam (2.74 g). Purification by flash chromatography on a 120 g silicacartridge eluting with 2-5% methanol in dichloromethane afforded 1.7 g(61%) of the title compound as a yellow powder. The title compound canadditionally be purified by recrystallization from acetonitrile. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 0.73-0.91 (m, 12H) 1.60-1.74 (m, 6H) 1.86-2.04(m, 6H) 2.17-2.30 (m, 4H) 2.52-2.53 (m, 4H) 2.84-3.02 (m, 4H) 3.52-3.56(m, 6H) 3.78-3.87 (m, 3H) 4.00-4.12 (m, 2H) 5.10-5.18 (m, 2H) 5.32-5.42(m, 2H) 5.88-5.95 (m, 2H) 7.05-7.33 (m, 11H) 7.41 (d, J=8.24 Hz, 1H)7.50 (d, J=8.35 Hz, 1H) 11.97-12.30 (m, 2H); MS (ESI+) m/z 1027 (M+H)⁺.

Example 5.2methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-[4-(4,4-diphenylpiperidin-1-yl)-3,5-difluorophenyl]-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

In a 100 mL round bottom was added(S)-6,6′-((2R,5R)-1-(4-(4,4-diphenylpiperidin-1-yl)-3,5-difluorophenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[c]imidazole)(0.385 g, 0.488 mmol), (S)-2-(methoxycarbonylamino)-3-methylbutanoicacid (0.180 g, 1.025 mmol), and 1H-benzo[d][1,2,3]triazol-1-ol hydrate(0.187 g, 1.220 mmol) in DMF (25 mL) to give an orange solution.4-Methylmorpholine (0.537 mL, 4.88 mmol) andN¹—((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochloride (0.234 g, 1.220 mmol) were added, and the mixture wasstirred at ambient temperature for 2 hours and then diluted with EtOAc.The organic solution was washed sequentially with saturated NaHCO₃, H₂O,and saturated NaCl. The organic layer was treated with 3-mercaptopropylsilica for 1 hour, dried (Na2SO₄), filtered and concentrated to a yellowfoam. Purification by flash chromatography on a 24 g silica cartridgeeluting with 2-7% methanol in CH₂Cl₂ provided material that was 90% pureby HPLC. A second chromatography of selected fractions on a 12 g silicacartridge eluting with 2-5% methanol in CH₂Cl₂ gave the title compoundas a cream colored solid (100 mg, 17%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm0.76-0.91 (m, 12H) 1.68 (d, J=4.01 Hz, 2H) 1.85-2.07 (m, 6H) 2.19 (s,4H) 2.38 (s, 4H) 2.86 (s, 4H) 3.54 (s, 6H) 3.82 (s, 4 H) 4.06 (t, J=8.35Hz, 2H) 5.10-5.17 (m, 2H) 5.34 (d, J=7.16 Hz, 2H) 5.85 (d, J=12.79 Hz,2H) 6.84-7.54 (m, 20H) 12.06 (d, J=18.98 Hz, 2H); MS (ESI+) m/z 1103(M+H)⁺.

Example 5.3methyl{(2S,3R)-1-[(2S)-2-{5-[(2R,5R)-1-[3,5-difluoro-4-(4-phenylpiperidin-1-yl)phenyl]-5-(2-{(2S)-1-[N-(methoxycarbonyl)-O-methyl-L-threonyl]pyrrolidin-2-yl}-1H-benzimidazol-5-yl)pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methoxy-1-oxobutan-2-yl}carbamate

(S)-6,6′-((2R,5R)-1-(3,5-Difluoro-4-(4-phenylpiperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole)hydrochloride (0.12 g) was dissolved in dimethyl sulfoxide (2 mL) andtreated with diisopropylethylamine (0.195 mL, 1.12 mmol) at ambienttemperature followed by(2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid (0.059 g, 0.307mmol) and HATU (0.112 g, 0.293 mmol). After 1 hour, the solution wasdiluted with water and extracted into dichloromethane, concentrated andpurified by chromatography, eluting with 0-8% methanol indichloromethane to give 0.071 g of a yellow solid (48%). ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.03 (dd, J=18.22, 6.18 Hz, 6H) 1.63-1.72 (m, 6H)1.99-2.08 (m, 6H) 2.15-2.26 (m, 6H) 2.87-3.00 (m, 2H) 3.10 (s, 3H) 3.15(s, 3H) 3.17-3.20 (m, 1H) 3.43-3.52 (m, 2H) 3.54 (s, 6 H) 3.79-3.89 (m,4H) 4.25-4.30 (m, 2H) 5.11-5.18 (m, 2H) 5.35-5.42 (m, 2H) 5.87-5.95 (m,2H) 7.09 (t, J=8.19 Hz, 2H) 7.12-7.32 (m, 9H) 7.41 (d, J=8.35 Hz, 1H)7.49 (d, J=8.78 Hz, 1H) 12.03 (s, 1H) 12.10 (s, 1H); MS (ESI+) m/z1059.4 (M+H)⁺.

Example 5.4methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-[3,5-difluoro-4-(4-phenylpiperidin-1-yl)phenyl]-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl}carbamate

(S)-6,6′-((2R,5R)-1-(3,5-Difluoro-4-(4-phenylpiperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole)hydrochloride (0.12 g) was dissolved in dimethyl sulfoxide (2 mL) andtreated with diisopropylethylamine (0.195 mL, 1.12 mmol) at ambienttemperature followed by(S)-2-(methoxycarbonylamino)-3,3-dimethylbutanoic acid (0.058 g, 0.307mmol) and HATU (0.112 g, 0.293 mmol). After 1 hour, the solution wasdiluted with water and extracted into dichloromethane. The organicphases were concentrated and purified by chromatography, eluting with0-6% methanol in dichloromethane to give the title compound (0.065 g,44%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.89 (d, J=13.88Hz, 18H) 1.61-1.73 (m, 8H) 1.95-2.08 (m, 4H) 2.15-2.24 (m, 6H) 2.86-3.02(m, 4H) 3.55 (s, 6H) 3.78-3.85 (m, 4H) 4.23 (dd, J=8.89, 4.66 Hz, 2H)5.13-5.22 (m, 2H) 5.33-5.43 (m, 2H) 5.92 (dd, J=12.85, 2.98 Hz, 2H)7.05-7.18 (m, 4H) 7.20-7.29 (m, 5H) 7.33 (s, 1H) 7.42 (d, J=8.13 Hz, 1H)7.49 (d, J=8.46 Hz, 1H) 12.05 (d, J=1.63 Hz, 1H) 12.09 (d, J=1.30 Hz,1H); MS (ESI+) m/z 1055.4 (M+H)⁺.

Example 5.5methyl{(2S)-1-[(2S,4R)-2-{5-[(2R,5R)-1-[3,5-difluoro-4-(piperidin-1-yl)phenyl]-5-{2-[(2S,4R)-4-methoxy-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}-4-methoxypyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

(S)-6,6′-((2R,5R)-1-(3,5-Difluoro-4-(piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((2S,4R)-4-methoxypyrrolidin-2-yl)-1H-benzo[c]imidazole)(0.20 g, 0.287 mmol) was dissolved in dimethyl sulfoxide (3 mL) andtreated with diisopropylethylamine (0.400 mL, 2.29 mmol) at ambienttemperature followed by (S)-2-(methoxycarbonylamino)-3-methylbutanoicacid (0.111° g, 0.631 mmol) and HATU (0.229 g, 0.603 mmol). After 2hours, the solution was diluted with water and extracted intodichloromethane. The organic layer was concentrated and purified bychromatography, eluting with 0-6% methanol in dichloromethane to givethe title compound (0.163 g, 56%) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.71-0.84 (m, 12H) 1.35-1.49 (m, 8H) 1.69 (d, J=5.42 Hz,2H) 1.83-1.94 (m, 2H) 2.22-2.32 (m, 4H) 2.76 (s, 4H) 3.29 (s, 6H) 3.54(s, 6H) 3.87 (dd, J=11.11, 3.85 Hz, 2H) 4.03 (q, J=7.05 Hz, 4H) 4.21 (s,2H) 5.02-5.15 (m, 2H) 5.36 (d, J=3.25 Hz, 2H) 5.84-5.94 (m, 2H)7.04-7.11 (m, 2H) 7.19 (s, 1H) 7.27-7.34 (m, 3H) 7.41 (d, J=8.24 Hz, 1H)7.48 (d, J=8.24 Hz, 1H) 12.13 (s, 1H) 12.19 (s, 1H); MS (ESI+) m/z1011.6 (M+H)⁺.

Example 5.6dimethyl({(2R,5R)-1-[3,5-difluoro-4-(piperidin-1-yl)phenyl]pyrrolidine-2,5-diyl}bis{1H-benzimidazole-5,2-diyl(2S)pyrrolidine-2,1-diyl[(1S)-1-cyclohexyl-2-oxoethane-2,1-diyl]})biscarbamate

(S)-6,6′-((2R,5R)-1-(3,5-Difluoro-4-(piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole)(0.192 g, 0.302 mmol) was dissolved in dimethyl sulfoxide (4 mL) andtreated with diisopropylethylamine (0.421 mL, 2.41 mmol) at ambienttemperature followed by (S)-2-cyclohexyl-2-(methoxycarbonylamino)aceticacid (0.143 g, 0.663 mmol) and HATU (0.241 g, 0.633 mmol). After 1 hour,the solution was diluted with water and extracted into dichloromethane.The organic phase was concentrated, and the residue was purified bychromatography, eluting with 0-8% methanol in dichloromethane to givethe title compound (0.166 g, 53%) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.80-1.12 (m, 8H) 1.36-1.70 (m, 24H) 1.98 (d, J=4.45 Hz,4 H) 2.15-2.25 (m, 4H) 2.75 (s, 4H) 3.52 (s, 6H) 3.81 (d, J=2.39 Hz, 4H)4.08 (q, J=8.57 Hz, 2H) 5.14 (d, J=4.23 Hz, 2H) 5.36 (d, J=3.58 Hz, 2H)5.82-5.93 (m, 2H) 7.10 (dd, J=13.93, 8.30 Hz, 2 H) 7.15-7.28 (m, 4H)7.42 (d, J=7.37 Hz, 1H) 7.48 (dd, J=8.35, 1.84 Hz, 1H) 12.00 (s, 1H)12.16 (s, 1H); MS (ESI+) m/z 1031.4 (M+H)⁺.

Example 5.7methyl{(2S)-1-[(2S)-2-{6-[(2R,5R)-1-[4-(3,5-dimethylpiperidin-1-yl)-3,5-difluorophenyl]-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-6-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

Diisopropylethylamine (3 mL, 17.18 mmol) was added to a suspension of(S)-6,6′-((2R,5R)-1-(4-(3,5-dimethylpiperidin-1-yl)-3,5-difluorophenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole)(1.045 g, 1.572 mmol), (S)-2-(methoxycarbonylamino)-3-methylbutanoicacid (0.6852 g, 3.91 mmol), and HATU (1.4995 g, 3.94 mmol) indichloromethane (20 mL). The reaction mixture was stirred at ambienttemperature for 30 minutes. The reaction was diluted withdichloromethane, washed with water (2×), brine (1×), and concentrated.The residue was purified by flash chromatography (2-5%methanol/dichloromethane) to afford the title compound (0.7107 g, 46%).¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.50 (q, J=11.9, 1H), 0.97-0.64 (m,18H), 1.32-1.20 (m, 2H), 1.81-1.46 (m, 5H), 2.09-1.80 (m, 6H), 2.32-2.13(m, 5H), 2.75 (dd, J=10.0, 40.2, 2H), 3.18-3.05 (m, 1H), 3.54 (s, 6H),3.82 (s, 4H), 4.14-3.95 (m, 2H), 5.14 (s, 2H), 5.36 (d, J=7.2, 2H), 5.88(d, J=12.8, 2H), 7.14-7.02 (m, 2H), 7.19 (s, 1H), 7.33-7.23 (m, 3H),7.41 (d, J=8.2, 1H), 7.49 (d, J=8.2, 1H), 12.37-11.98 (m, 2H); MS (ESI+)m/z 979 (M+H)⁺.

Example 5.8methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-{3,5-difluoro-4-[4-(trifluoromethyl)piperidin-1-yl]phenyl}-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

(S)-6,6′-((2R,5R)-1-(3,5-Difluoro-4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole)tetrahydrochloride (250 mg, 0.294 mmol) and

-   (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (113 mg, 0.647    mmol) were combined in anhydrous DMF (3 mL) under nitrogen. HOBT    hydrate (113 mg, 0.735 mmol) and EDAC (144 mg, 0.735 mmol) were    added. The amber-colored solution was cooled to 0° C.    4-Methylmorpholine (0.323 mL, 2.94 mmol) was added, the cooling bath    was removed, and the reaction mixture was stirred at 20° C. After 2    hours, the reaction was diluted with EtOAc (50 mL) and washed with    water (3×25 mL) and brine (25 mL). The organic phase was dried over    anhydrous MgSO₄, filtered, and concentrated by rotary evaporation to    a tan solid (300 mg). An aliquot (50 mg) of crude material was    dissolved in 2 mL acetonitrile and 2 mL 0.1% TFA in H₂O, and    purified by RP-LC18HPLC (Waters Prep LC, 40 mm Module with Nova-Pak    HR C18 6 μm 40×100 mm Prep Pak cartridge) eluting with a 30 minutes    gradient of 95:5 0.1% TFA in H₂O/acetonitrile to 25:75 0.1% TFA in    H₂O/acetonitrile, then 10 minutes to 100% acetonitrile at 20    mL/minute (10 mL fractions). Pure fractions were treated with    saturated aq NaHCO₃ (2 mL/tube), each tube was vortexed to    thoroughly neutralize TFA, and the neutralized solutions were    combined in a 250-mL round bottom flask. The acetonitrile was    removed by rotary evaporation, and extracted the remaining aqueous    phase with EtOAc (2×50 mL). The combined organic extracts were dried    over anhydrous MgSO₄, filtered, and concentrated by rotary    evaporation to afford the title compound as a white solid (18 mg).    Repeated purification of an additional 100 mg as above by prep-HPLC    in two 50-mg injections. Workup as above afforded additional title    compound as a white solid (34 mg). ¹H NMR (400 MHz, DMSO-d₆) δ ppm    0.73-0.90 (m, 12H), 1.23 (s, 1H), 1.34-1.49 (m, 2H), 1.63-1.76 (m,    4H), 1.83-2.04 (m, 6H), 2.11-2.25 (m, 4H), 2.84 (m, 4H), 3.52 (s,    6H), 3.81 (br s, 4H), 4.00-4.09 (m, 2H), 5.08-5.18 (m, 2H),    5.28-5.42 (m, 2H), 5.89 (d, J=12.79 Hz, 2H), 7.06 (t, J=7.26 Hz,    2H), 7.16-7.32 (m, 4H), 7.39 (d, J=8.24 Hz, 1H), 7.47 (d, J=8.13 Hz,    1H), 12.06 (two s, 2H); MS (ESI+) m/z 1019 (M+H)⁺.

Example 5.9methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-[4-(4-tert-butylpiperidin-1-yl)-3,5-difluorophenyl]-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

(S)-6,6′-((2R,5R)-1-(4-(4-tert-Butylpiperidin-1-yl)-3,5-difluorophenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole)tetrahydrochloride (250 mg, 0.298 mmol) and

-   (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (115 mg, 0.656    mmol) were combined in anhydrous DMF (3 mL) under nitrogen. HOBT    hydrate (114 mg, 0.745 mmol) and EDAC (146 mg, 0.745 mmol) were    added, and then the amber-colored solution was cooled to 0° C.    4-Methylmorpholine (0.328 mL, 2.98 mmol) was added, the cooling bath    was removed, and the reaction mixture was stirred at 20° C. After 18    hours, the reaction mixture was diluted with EtOAc (50 mL), washed    with water (3×25 mL) and brine (25 mL). The organic phase was dried    over anhydrous MgSO₄, filtered, and concentrated by rotary    evaporation to a yellow solid. Pre-purified by SiO₂ flash    chromatography (Alltech Extract-Clean™ column, 10 g bed) eluting    with 3% CH₃OH/CH₂Cl₂ afforded a yellow solid (119 mg). An aliquot    (50 mg) of the residue was dissolved in 2 mL acetonitrile and 2 mL    0.1% TFA in H₂O, and purified by RP-C18HPLC (Waters Prep LC, 40 mm    Module with Nova-Pak HR C18 6 μm 40×100 mm Prep Pak cartridge)    eluting with a 30 minutes gradient of 95:5 0.1% TFA in    H₂O/acetonitrile to 25:75 0.1% TFA in H₂O/acetonitrile, then 10    minutes to 100% acetonitrile at 20 mL/minute (10 mL fractions). Pure    fractions were treated with saturated aq NaHCO₃ (2 mL/tube), each    tube was vortexed to thoroughly neutralize TFA, and the solutions    were combined in a 250-mL round bottom flask. The remaining 69 mg of    material was purified by prep-HPLC as described above. The pure    product-containing fractions were treated with saturated aq NaHCO₃    as above and combined in the same 250-mL round bottom flask. The    acetonitrile was removed by rotary evaporation, the remaining    aqueous phase was extracted with EtOAc (2×50 mL). The combined    organic extracts were dried over anhydrous MgSO₄, filtered, and    concentrated by rotary evaporation to afford the title compound as a    white solid (56 mg). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.68-0.93 (m,    22H), 1.09-1.25 (m, 2H), 1.53 (d, J=11.93 Hz, 2H), 1.63-1.75 (m,    2H), 1.80-2.08 (m, 7H), 2.12-2.27 (m, 4H), 2.71-2.91 (m, 5H), 3.54    (s, 6H), 3.82 (br s, 4H), 4.06 (t, J=8.35 Hz, 2H), 5.09-5.19 (m,    2H), 5.30-5.44 (m, 2H), 5.89 (d, J=12.69 Hz, 2H), 7.02-7.11 (m, 2H),    7.17-7.32 (m, 4H), 7.40 (d, J=8.24 Hz, 1H), 7.49 (d, J=8.13 Hz, 1H),    12.07 (two s, 2H); MS (ESI+) m/z 1007 (M+H)⁺.

Example 5.10methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-[4-(4,4-dimethylpiperidin-1-yl)-3,5-difluorophenyl]-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

(S)-6,6′-((2R,5R)-1-(4-(4,4-Dimethylpiperidin-1-yl)-3,5-difluorophenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole)pentahydrochloride (250 mg, 0.295 mmol) and(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (109 mg, 0.620 mmol)were combined in anhydrous DMF (3 mL) under nitrogen. HOBT hydrate (104mg, 0.679 mmol), and EDAC (133 mg, 0.679 mmol) were added, and then theamber-colored solution was cooled to 0° C. 4-Methylmorpholine (0.325 mL,2.95 mmol) was added, the cooling bath was removed, and the reactionmixture was stirred at 20° C. After 2 hours, the reaction mixture wasdiluted with EtOAc (50 mL), and washed with water (3×25 mL) and brine(25 mL). The organic phase was dried over anhydrous MgSO₄, filtered, andconcentrated by rotary evaporation to a tan solid. Purification by SiO₂flash chromatography (3.8 cm×15 cm) eluting with a step gradient of 3%to 4% CH₃OH/CH₂Cl₂ afforded the title compound as a solid (115 mg). Analiquot (50 mg) was dissolved in 1.5 mL acetonitrile and 1.5 mL 0.1% TFAin H₂O, and purified by RP-C18HPLC (Waters Prep LC, 40 mm Module withNova-Pak HR C18 6 μm 40×100 mm Prep Pak cartridge) eluting with a 30minutes gradient of 95:5 0.1% TFA in H₂O/acetonitrile to 25:75 0.1% TFAin H₂O/acetonitrile, then 10 minutes, to 100% acetonitrile at 20mL/minute (10 mL fractions). Pure fractions were treated with saturatedaq NaHCO₃ (2 mL/tube), each tube was vortexed to thoroughly neutralizeTFA, and the solutions were combined in a 250-mL round bottom flask.Acetonitrile was removed by concentration in vacuo. The remainingaqueous phase was extracted with EtOAc (2×50 mL). The combined organicextracts were dried over anhydrous MgSO₄, filtered, and concentrated byrotary evaporation to afford the title compound as a white solid (33mg). The remaining 65 mg of impure product (from silica gel column) werepurified by RP-C18 prep HPLC as described above to obtain additionaltitle compound as a white solid (33 mg). ¹H NMR (400 MHz, DMSO-d₆) δ ppm0.75-0.91 (m, 12H), 0.87 (s, 6H), 1.21-1.35 (m, 4H), 1.63-1.77 (m, 2H),1.81-2.09 (m, 6H), 2.11-2.29 (m, 4H), 2.49-2.59 (m, 2H), 2.76 (s, 4H),3.54 (s, 6H), 3.82 (br s, 4H), 4.06 (t, J=8.46 Hz, 2H), 5.09-5.22 (m,2H), 5.30-5.44 (m, 2H), 5.89 (d, J=12.79 Hz, 2H), 7.03-7.11 (m, 2H),7.17-7.32 (m, 4H), 7.41 (d, J=8.13 Hz, 1H), 7.49 (d, J=8.02 Hz, 1H),12.07 (two s, 2H); (ESI+) m/z 979 (M+H)⁺; MS (ESI−) m/z 977 (M−H)⁻.

Example 5.11methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-[4-(6-azaspiro[2,5]oct-6-yl)-3,5-difluorophenyl]-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

(S)-6,6′-((2R,5R)-1-(3,5-Difluoro-4-(6-azaspiro[2.5]octan-6-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole)tetrahydrochloride (250 mg, 0.309 mmol) and(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (119 mg, 0.680 mmol)were combined in anhydrous DMF (3 mL) under nitrogen. HOBT hydrate (118mg, 0.773 mmol) and EDAC (151 mg, 0.773 mmol), were added, and then theamber-colored solution was cooled to 0° C. 4-Methylmorpholine (0.340 mL,3.09 mmol) was added, the cooling bath was removed, and the reactionmixture was stirred at 20° C. After 16.5 hours, the reaction mixture wasdiluted with EtOAc (50 mL), and washed with water (3×25 mL) and brine(25 mL). The organic phase was dried over anhydrous MgSO₄, filtered, andconcentrated by rotary evaporation to a yellow solid. Pre-purificationby SiO₂ flash chromatography (Alltech Extract-Clean™ column, 10 g bed)eluting with 3% CH₃OH/CH₂Cl₂ to afforded a beige solid (172 mg). Analiquot (50 mg) was dissolved in 1.5 mL acetonitrile and 1.5 mL 0.1% TFAin H₂O, and purified by RP-C18HPLC (Waters Prep LC, 40 mm Module withNova-Pak HR C18 6 μm 40×100 mm Prep Pak cartridge) eluting with a 30minutes gradient of 95:5 0.1% TFA in H₂O/acetonitrile to 25:75 0.1% TFAin H₂O/acetonitrile, then 10 minutes to 100% acetonitrile at 20mL/minute (10 mL fractions). Pure fractions were treated with saturatedaq NaHCO₃ (2 mL/tube), each tube was vortexed to thoroughly neutralizeTFA, and the solutions were combined in a 250-mL round bottom flask. Twoadditional 50 mg lots were purified by prep-HPLC as described above, andthe pure product-containing fractions were treated with saturated aqNaHCO₃ as above and combined in the same 250-mL round bottom flask. Theacetonitrile was removed by concentration in vacuo, and the remainingaqueous phase was extracted with EtOAc (2×50 mL). The combined organicphases were dried over anhydrous MgSO₄, filtered, and concentrated byrotary evaporation to afford the title compound as a white solid (42mg). ¹N NMR (400 MHz, DMSO-d₆) δ ppm 0.22 (s, 4H), 0.72-0.93 (m, 12H),1.21-1.36 (m, 5H), 1.61-1.78 (m, 2H), 1.83-2.08 (m, 7H), 2.13-2.27 (m,4H), 2.81 (br s, 4H), 3.53 (s, 6H), 3.82 (br s, 4H), 4.06 (t, J=8.40 Hz,2H), 5.10-5.19 (m, 2H), 5.29-5.45 (m, 2H), 5.90 (d, J=12.79 Hz, 2H),7.02-7.32 (m, 6H), 7.41 (d, J=8.24 Hz, 1H), 7.49 (d, J=8.24 Hz, 1H),12.07 (two s, 2H); MS (ESI+) m/z 977 (M+H)⁺.

Example 5.12methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-[4-(3-azaspiro[5.5]undec-3-yl)-3,5-difluorophenyl]-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

(S)-6,6′-((2R,5R)-1-(3,5-Difluoro-4-(3-azaspiro[5.5]undecan-3-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole)tetrahydrochloride (250 mg, 0.294 mmol) and(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (113 mg, 0.646 mmol)were combined in anhydrous DMF (3 mL) under nitrogen. HOBT hydrate (113mg, 0.735 mmol) and EDAC (144 mg, 0.735 mmol), were added, and then themixture was cooled to 0° C. 4-Methylmorpholine (0.323 mL, 2.94 mmol) wasadded, the cooling bath was removed, and the reaction mixture wasstirred at 20° C. for 18 hours. The reaction mixture was diluted withEtOAc (50 mL) and washed with water (3×25 mL) and brine (25 mL). Theorganic phase was dried over anhydrous MgSO₄, filtered, and concentratedby rotary evaporation to a beige foam. The crude material was purifiedby SiO₂ flash chromatography (3.8 cm×15 cm) eluting with 4% CH₃OH/CH₂Cl₂to afford the title compound as a white solid (82 mg). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.72-0.93 (m, 12H), 1.22-1.41 (m, 15 H), 1.63-1.74 (m,2H), 1.80-2.07 (m, 7H), 2.12-2.27 (m, 4H), 2.75 (s, 4H), 3.54 (s, 6H),3.82 (s, 4H), 4.06 (t, J=8.40 Hz, 2H), 5.14 (d, J=1.19 Hz, 2H),5.27-5.42 (m, 2H), 5.88 (d, J=12.69 Hz, 2H), 7.03-7.11 (m, 2H), 7.20 (s,1H), 7.29 (d, J=5.96 Hz, 3H), 7.40 (d, J=8.24 Hz, 1H), 7.49 (d, J=8.24Hz, 1H), 12.07 (m, 2H); MS (ESI+) m/z 1019 (M+H)⁺, (ESI−) m/z 1017(M−H)⁻.

Example 5.13methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-[4-(1,3-dihydro-2H-isoindol-2-yl)-3,5-difluorophenyl]-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

(S)-6,6′-((2R,5R)-1-(3,5-Difluoro-4-(isoindolin-2-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole)tetrahydrochloride (250 mg, 0.306 mmol) and(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (118 mg, 0.673 mmol)were combined in anhydrous DMF (3 mL) under nitrogen. HOBT hydrate (117mg, 0.765 mmol) and EDAC (150 mg, 0.765 mmol) were added, then theamber-colored solution was cooled to 0° C. 4-Methylmorpholine (0.337 mL,3.06 mmol) was added, the cooling bath was removed, and the reactionmixture was stirred at 20° C. for 16 hours. The reaction mixture wasdiluted with EtOAc (50 mL) and this mixture was washed with water (3×25mL) and brine (25 mL). The organic phase over dried over anhydrousMgSO₄, filtered, and concentrated by rotary evaporation to agreenish-yellow solid. The solid was purified by SiO₂ flashchromatography (3.8 cm×15 cm) eluting with 4% CH₃OH/CH₂Cl₂ to afford anoff-white solid (104 mg). An aliquot (52 mg) was dissolved acetonitrile(2 mL) and 0.1% TFA in H₂O (2 mL) and purified by RP-C18HPLC (WatersPrep LC, 40 mm Module with Nova-Pak HR C18 6 μm 40×100 mm Prep Pakcartridge) eluting with a 30 minutes gradient of 95:5 0.1% TFA inH₂O/acetonitrile to 25:75 0.1% TFA in H₂O/acetonitrile, then 10 minutesto 100% acetonitrile at 20 mL/minute (10 mL fractions). Pure fractionswere treated with saturated aq NaHCO₃ (2 mL/tube), each tube wasvortexed to thoroughly neutralize TFA, and the solutions were combinedin a 500-mL round bottom flask. The remaining 52 mg of material werepurified by prep-HPLC as described above and the pure product-containingfractions were treated with saturated aq NaHCO₃ as described above. Theproduct containing fractions were combined in the same 500-mL roundbottom flask. The acetonitrile was removed by rotary evaporation. Theremaining aqueous phase was extracted with EtOAc (2×50 mL). The combinedorganic phases were dried over anhydrous MgSO₄, filtered, andconcentrated by rotary evaporation to afford the title compound as awhite solid (88 mg). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.75-0.92 (m, 12H),1.61-2.08 (m, 8H), 2.11-2.26 (m, 3H), 2.57 (s, 2H), 3.54 (s, 6H), 3.83(s, 4H), 4.07 (t, J=8.29 Hz, 2H), 4.26-4.43 (m, 4H), 5.10-5.23 (m, 2H),5.33-5.50 (m, 2H), 5.99 (d, J=12.79 Hz, 2H), 7.09 (t, J=6.83 Hz, 2H),7.20 (s, 4H), 7.22-7.37 (m, 4H), 7.42 (d, J=8.24 Hz, 1H), 7.50 (d,J=8.13 Hz, 1H), 12.09 (m, 2H); MS (ESI+) m/z 985 (M+H)⁺, (ESI−) m/z 983(M−H)⁻.

Example 5.14methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-3,5-difluorophenyl]-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamatePart A

The compound8-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-1,4-dioxa-8-azaspiro[4.5]decanecan be transformed following the methods of General Procedure 8.1 andGeneral Procedure 9D (PtO2) to obtaindimethyl(2S,2′S)-1,1′-((2S,2′S)-2,2′-(4,4′-((2R,5R)-1-(3,5-difluoro-4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-amino-4,1-phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate.

Part B

In an oven-dried 10-mL round bottom flask, dimethyl((2R,5R)-1-(3,5-difluoro-4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-amino-4,1-phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate(200 mg, 0.191 mmol) was dissolved in anhydrous toluene (2 mL) undernitrogen. Glacial acetic acid (0.110 mL, 1.914 mmol) was added, and thesolution was stirred in an oil bath at 60° C. After 1.5 hours, thereaction mixture was cooled to room temperature, diluted with EtOAc (50mL), and washed with saturated aq NaHCO₃ (25 mL). The organic phase wasdried over anhydrous MgSO₄, filtered, and concentrated by rotaryevaporation to afford the crude title compound as a tan solid (185 mg).An aliquot (93 mg) of the impure material was dissolved acetonitrile (2mL) and 0.1% TFA in H₂O (2 mL) and purified by RP-C18HPLC (Waters PrepLC, 40 mm Module with Nova Pak HR C18 6 μm 40×100 mm Prep Pak cartridge)eluting with a 30 minutes gradient of 95:5 0.1% TFA in H₂O/acetonitrileto 25:75 0.1% TFA in H₂O/acetonitrile, then 10 minutes to 100%acetonitrile at 20 mL/minute. Pure fractions were immediately treatedwith saturated aq NaHCO₃ (2 mL/tube), each tube was vortexed tothoroughly neutralize TFA, and the solutions were combined in a 500-mLround bottom flask. The remaining 92 mg were purified bypreparative-HPLC as described above and the pure product-containingfractions were treated with saturated aq NaHCO₃ as described above. Theadditional fractions were combined in the same 500-mL round bottomflask. The acetonitrile was removed by rotary evaporation, and theremaining aqueous phase was extracted with EtOAc (2×50 mL). The combinedorganic extracts were dried over anhydrous MgSO₄, filtered, andconcentrated by rotary evaporation to afford the title compound as awhite solid (103 mg). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.73-0.94 (m,12H), 1.51-1.61 (m, 4 H), 1.63-1.75 (m, 2H), 1.83-2.10 (m, 8H),2.13-2.29 (m, 4H), 2.86 (s, 4H), 3.54 (s, 6H), 3.83 (s, 8H), 4.06 (t,J=8.51 Hz, 2H), 5.09-5.21 (m, 2H), 5.30-5.42 (m, 2H), 5.90 (d, J=12.69Hz, 2 H), 7.01-7.12 (m, 2H), 7.17-7.32 (m, 4H), 7.40 (s, 1H), 7.49 (d,J=8.24 Hz, 1H), 11.71-12.53 (m, 2H); MS (ESI+) m/z 1009 (M+H)⁺, (ESI−)m/z 1007 (M−H)⁻.

Example 5.15methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-[3,5-difluoro-4-(4-phenyl-3,6-dihydropyridin-1(2H)-yl)phenyl]-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamatePart A

The compound1-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-4-phenyl-1,2,3,6-tetrahydropyridinecan be transformed following the methods of General Procedure 8.1 andGeneral Procedure 9E to obtaindimethyl(2S,2′S)-1,1′-((2S,2′S)-2,2′-(4,4′-((2R,5R)-1-(3,5-difluoro-4-(4-phenyl-5,6-dihydropyridin-1(2H)-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-amino-4,1-phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate.

Part B

In an oven-dried 5-mL round bottom flask,dimethyl(2S,2′S)-1,1′-((2S,2′S)-2,2′-(4,4′-((2R,5R)-1-(3,5-difluoro-4-(4-phenyl-5,6-dihydropyridin-1(2H)-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-amino-4,1-phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate(75 mg, 0.071 mmol) was dissolved in anhydrous toluene (1 mL) undernitrogen. Glacial acetic acid (0.041 mL, 0.707 mmol) was added, and thesolution was stirred in an oil bath at 60° C. After 1.5 hours, theyellow reaction mixture was cooled to room temperature, diluted in EtOAc(50 mL), and washed with saturated aq NaHCO₃ (25 mL). The organic phasewas dried over anhydrous MgSO₄, filtered, and concentrated by rotaryevaporation to a yellow solid (˜80 mg). The residue was dissolved in 2mL acetonitrile and 2 mL 0.1% TFA in H₂O, and purified by RP-C18HPLC(Waters Prep LC, 40 mm Module with Nova-Pak HR C18 6 μm 40×100 mm PrepPak cartridge) eluting with a 30 minutes gradient of 95:5 0.1% TFA inH₂O/acetonitrile to 25:75 0.1% TFA in H₂O/acetonitrile, then 10 minutesto 100% acetonitrile at 20 mL/minute (10 mL fractions). Pure fractionswere treated with saturated aq NaHCO₃ (2 mL/tube), each tube wasvortexed to thoroughly neutralize TFA, and the solutions were combinedin a 250-mL round bottom flask. The acetonitrile was removed by rotaryevaporation, and the remaining aqueous phase was extracted with EtOAc(2×50 mL). The organic phase was dried over anhydrous MgSO₄, filtered,and concentrated by rotary evaporation to afford the product as anoff-white solid (34 mg). ¹H NMR (400 MHz, DMSO-d₅) δ ppm 0.76-0.94 (m,12H), 1.70 (d, J=4.55 Hz, 2H), 1.83-2.10 (m, 6H), 2.11-2.26 (m, 3H),2.44 (s, 1H), 2.56 (s, 4H), 3.09 (s, 2H), 3.48 (s, 2H), 3.54 (s, 6H),3.82 (s, 4H), 4.07 (t, J=8.35 Hz, 2H), 5.09-5.22 (m, 2H), 5.30-5.46 (m,2H), 5.95 (d, J=12.90 Hz, 2H), 6.09 (s, 1H), 7.04-7.17 (m, 2H),7.19-7.25 (m, 2H), 7.26-7.34 (m, 5H), 7.36-7.45 (m, 3H), 7.50 (d, J=8.35Hz, 1H), 11.71-12.63 (m, 2H); MS (ESI+) m/z 1025 (M+H)⁺, (ESI−) m/z 1023(M−H)⁻.

Example 6.1methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-(4-tert-butylphenyl)-5-{5-fluoro-2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-6-yl}pyrrolidin-2-yl]-6-fluoro-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

To6,6′-[(2R,5R)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis{5-fluoro-2-[(2S)-pyrrolidin-2-yl]-1H-benzimidazole}was added DMF (1.0 mL) followed by N-methylmorpholine (0.045 mL, 0.41mmol), (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (15 mg, 0.09mmol), EDC (20 mg, 0.1 mmol) and HOBT (16 mg, 0.1 mmol). The solutionwas stirred at room temperature for 18 hours. The reaction mixture wasdiluted with EtOAc, washed with H₂O and brine, dried (Na₂SO₄), filteredand concentrated. The product was purified by reverse-phase HPLCchromatography (5-100% CH₃CN/0.1% TFA-H₂O); the desired fractions wereneutralized with aqueous NaHCO₃ solution, extracted with EtOAc, dried,filtered and solvent evaporated to give the title compound (6.7 mg, 7.2μmol, 18%): ¹H NMR (400 MHz, CDCl₃) δ ppm 10.48 (m, 1H) 10.25 (m, 1H)7.39 (m, 1H) 7.14 (m, 1H) 6.98 (m, 3H) 6.29 (m, 1H) 5.54 (br s, 1H) 5.34(br s, 4H) 4.31 (m, 1H) 3.82 (m, 2H) 3.70 (s, 6H) 3.51-3.65 (m, 2H) 3.03(br s, 2H) 2.51 (br s, 2H) 2.23-2.40 (m, 2H) 2.14 (m, 4H) 1.95 (m, 4H)1.27 (m, 2H) 1.09-1.23 (m, 9H) 1.07 (m, 3H) 0.87 (m, 9H) 0.67-0.79 (m,2H); MS (ESI) m/z 924 (M+H)⁺.

Example 6.2methyl{(2S)-1-[(2S)-2-{5-[(2R,5S)-1-(4-tert-butylphenyl)-5-{5-fluoro-2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-6-yl}pyrrolidin-2-yl]-6-fluoro-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

From the HPLC purification of Example 6.1, the cis isomer (6.4 mg, 6.9μmol, 17%) was also obtained: ¹H NMR (400 MHz, CDCl₃) δ ppm 11.62 (s,1H) 11.37 (s, 1H) 7.45-7.55 (m, 3H) 7.36 (d, 1H) 7.04 (d, 2H) 6.92 (d,1H) 6.77 (d, 1H) 6.41 (d, 2H) 5.36-5.40 (m, 2H) 5.33 (m, 1H) 5.07 (t,1H) 3.98-4.07 (m, 1H) 3.93 (m, 1H) 3.74-3.86 (m, 2H) 3.72 (m, 11-1) 3.59(m, 2H) 2.80 (m, 1H) 2.50 (s, 6H) 2.32 (s, 4H) 1.86-2.27 (m, 7H) 1.78(m, 1H) 1.17 (s, 9H) 0.86-1.01 (m, 9H); MS (ESI) m/z 924 (M+H)⁺.

The following example compounds 6.3-6.11 can be made from theappropriate listed intermediate amine following generally the method ofExample 6.1:

Intermediate amines:

-   6,6′-[(2R,5R)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis{7-fluoro-2-[(2S)-pyrrolidin-2-yl]-1H-benzimidazole}    (ACD Name v12);-   6,6′-[(2R,5S)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis{7-fluoro-2-[(2S)-pyrrolidin-2-yl]-1H-benzimidazole}    (ACD Name v12);-   6,6′-[(2R,5R)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis{7-chloro-2-[(2S)-pyrrolidin-2-yl]-1H-benzimidazole}    (ACD Name v12);-   6,6′-[(2R,5S)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis{7-chloro-2-[(2S)-pyrrolidin-2-yl]-1H-benzimidazole}    (ACD Name v12);-   6,6′-[(2R,5R)-1-(4-tert-butylphenyl    pyrrolidine-2,5-diyl]bis{7-methyl-2-[(2S)-pyrrolidin-2-yl]-1H-benzimidazole}    (ACD Name v12);-   6,6′-[(2R,5S)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis{7-methyl-2-[(2S)-pyrrolidin-2-yl]-1H-benzimidazole}    (ACD Name v12);-   6,6′-{(2R,5R)-1-[3-fluoro-4-(piperidin-1-yl)phenyl]pyrrolidine-2,5-diyl}bis{5-fluoro-2-[(2S)-pyrrolidin-2-yl]-1H-benzimidazole}    (ACD Name v12);-   6,6′-{(2R,5R)-1-[3,5-difluoro-4-(piperidin-1-yl)phenyl]pyrrolidine-2,5-diyl}bis{5-fluoro-2-[(2S)-pyrrolidin-2-yl]-1H-benzimidazole}    (ACD Name v12); and-   6,6′-{(2R,5R)-1-[3,5-difluoro-4-(4-phenylpiperidin-1-yl)phenyl]pyrrolidine-2,5-diyl}bis{5-fluoro-2-[(2S)-pyrrolidin-2-yl]-1H-benzimidazole}    (ACD Name v12).

Example 6.3methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-(4-tert-butylphenyl)-5-{7-fluoro-2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-6-yl}pyrrolidin-2-yl]-4-fluoro-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, CDCl₃) δ ppm 10.41-10.64 (m, 2H) 6.84-7.06 (m, 6H)6.25-6.36 (m, 2H) 5.55-5.68 (m, 1H) 5.25-5.46 (m, 4H) 4.27-4.40 (m, 1H)3.79-3.92 (m, 2H) 3.71 (s, 6H) 3.56-3.67 (m, 2H) 3.03-3.27 (m, 2H)1.83-2.66 (m, 10H) 1.14 (s, 9H) 0.77-1.31 (m, 14H); MS (ESI) m/z 924(M+H)⁻.

Example 6.4methyl{(2S)-1-[(2S)-2-{5-[(2R,5S)-1-(4-tert-butylphenyl)-5-{7-fluoro-2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-6-yl}pyrrolidin-2-yl]-4-fluoro-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, CDCl₃) δ ppm 10.54-10.71 (m, 2H) 7.54-7.68 (m, 2H)7.00-7.21 (m, 4H) 6.43-6.54 (m, 2H) 5.27-5.50 (m, 4H) 5.20 (br s, 2H)4.29-4.42 (m, 1H) 3.80-3.94 (m, 2H) 3.71 (s, 6H) 3.59-3.69 (m, 2H)3.04-3.29 (m, 2H) 1.86-2.66 (m, 10H) 1.18 (s, 9H) 0.79-1.33 (m, 14H); MS(ESI) m/z 924 (M+H)⁺.

Example 6.5methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-(4-tert-butylphenyl)-5-{4-chloro-2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-4-chloro-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ 12.70 (s, OH), 12.39 (s, 1H), 8.07 (s, 1H),7.32 (dd, J=26.1, 8.1, 3H), 6.91 (d, J=37.0, 4H), 6.08 (d, J=7.9, 1H),5.64 (s, 1H), 5.17 (s, 1H), 4.66 (s, 1H), 4.10 (d, J=5.2, 1H), 3.86 (s,3H), 3.52 (d, J=14.1, 6H), 3.17 (d, J=5.2, 1H), 2.30-2.10 (m, 2H), 2.00(s, 4H), 1.77 (s, 1H), 1.23 (s, 1H), 1.18-1.01 (m, 9H), 1.01-0.72 (m,11H); MS (APCI+) m/z 958.76 (M+H)⁺.

Example 6.6methyl{(2S)-1-[(2S)-2-{5-[(2R,5S)-1-(4-tert-butylphenyl)-5-{4-chloro-2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-4-chloro-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ 12.45 (s, 1H), 8.06 (d, J=3.3, 1H), 7.68 (d,J=8.6, 2H), 7.48 (t, J=12.5, 2H), 7.31 (d, J=8.2, 2H), 7.00 (d, J=8.1,2H), 6.20 (d, J=8.7, 2H), 5.16 (d, J=32.0, 4H), 4.66 (s, 1H), 4.11 (s,1H), 3.88 (s, 3H), 3.56 (d, J=8.1, 6H), 2.30-2.09 (m, 5H), 2.02 (s, 7H),1.80 (s, 2H), 1.23 (s, 2H), 1.09 (s, 9H), 1.00-0.78 (m, 12H); MS (APCI+)m/z 958.64 (M+H)⁺.

Example 6.7methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-(4-tert-butylphenyl)-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-4-methyl-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-4-methyl-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.78-1.05 (m, 14H), 1.06 (s, 9H),1.86-2.06 (m, 8H), 2.09-2.31 (m, 4H), 2.58-2.72 (m, 6H), 3.54 (s, 6H),3.79-3.93 (m, 4H), 4.02-4.17 (m, 2H), 5.11-5.23 (m, 2H), 5.42-5.51 (m,2H), 6.02-6.12 (m, 2H), 6.71-6.83 (m, 2H), 6.83-6.96 (m, 2H), 7.04-7.19(m, 2H), 7.24-7.35 (m, 2H), 11.84-12.26 (m, 2H).

Example 6.8methyl{(2S)-1-[(2S)-2-{5-[(2R,5S)-1-(4-tert-butylphenyl)-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-4-methyl-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-4-methyl-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.79-1.06 (m, 12H), 1.23 (s, 9H),1.87-2.31 (m, J=30.69 Hz, 12H), 2.58-2.65 (m, J=3.25 Hz, 6H), 3.55 (s,6H), 3.81-3.96 (m, 4H), 4.01-4.19 (m, 2H), 4.92 (s, 2H), 5.12-5.26 (m,2H), 6.14-6.26 (m, 2H), 6.86-7.02 (m, 2H), 7.22-7.39 (m, 4H), 7.57-7.79(m, 2H), 11.90-12.32 (m, 2H); MS (ESI) m/z=916.4 (M+H)⁺.

Example 6.9methyl{(2S)-1-[(2S)-2-(6-fluoro-5-{(2R,5R)-5-{6-fluoro-2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}-1-[3-fluoro-4-(piperidin-1-yl)phenyl]pyrrolidin-2-yl}-1H-benzimidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, CDCl₃) δ ppm 10.21-10.67 (m, 2H) 6.55-7.99 (m, 6H)5.95-6.14 (m, 1H) 5.19-5.56 (m, 6H) 4.25-4.39 (m, 1H) 3.77-3.92 (m, 2H)3.70 (s, 6H) 3.42-3.76 (m, 3H) 2.95-3.17 (m, 2H) 2.64-2.95 (m, 2H)2.43-2.64 (m, 1H) 1.78-2.42 (m, 11H) 0.62-1.78 (m, 18H); MS (ESI) m/z969 (M+H)⁺.

Example 6.10methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-[3,5-difluoro-4-(piperidin-1-yl)phenyl]-5-{6-fluoro-2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-6-fluoro-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

To a solution of6,6′-{(2R,5R)-1-[3,5-difluoro-4-(piperidin-1-yl)phenyl]pyrrolidine-2,5-diyl}bis{5-fluoro-2-[(2S)-pyrrolidin-2-yl]-1H-benzimidazole}(64 mg, 0.095 mmol) in DMF (2378 μL) was added(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (35.0 mg, 0.200mmol), EDC (45.6 mg, 0.238 mmol), HOBT (36.4 mg, 0.238 mmol) andN-methylmorpholine (105 tit, 0.951 mmol), and the resultant solution wasstirred at ambient temperature overnight. The reaction solution wasdiluted with EtOAc, washed with H₂O and brine, dried (MgSO₄), filteredand concentrated. The crude material was dissolved in 1:1 CH₃CN:0.1%TFA/H₂O and purified by HPLC (C18, 0-100% CH₃CN/0.1% TFA/H₂O). Theproduct containing fractions were combined, made basic with saturatedsodium bicarbonate solution, and extracted with EtOAc. The organic layerwas dried (MgSO₄), filtered and concentrated to give the title compound(43.3 mg, 0.044 mmol, 46.1% yield). The title compound can also beprepared according to General Procedure 12C described above. ¹H NMR (400MHz, CDCl₃) δ ppm 10.25-10.70 (m, 2H) 6.83-7.53 (m, 4H) 5.70-5.91 (m,2H) 5.20-5.52 (m, 4H) 4.21-4.42 (m, 2H) 3.70 (s, 6H) 3.53-3.94 (m, 6H)1.75-3.17 (m, 16H) 0.63-1.74 (m, 18H); MS (ESI) m/z 987 (M+H)⁺.

Example 6.11methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-[3,5-difluoro-4-(4-phenylpiperidin-1-yl)phenyl]-5-{6-fluoro-2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-6-fluoro-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, CDCl₃) δ ppm 10.54 (br s, 2H) 7.09-7.33 (m, 9H)5.77-5.92 (m, 2H) 5.23-5.52 (m, 4H) 4.24-4.39 (m, 2H) 3.79-3.91 (m, 2H)3.70 (s, 6H) 3.55-3.67 (m, 2H) 2.92-3.21 (m, 5H) 1.73-2.65 (m, 10H)0.97-1.74 (m, 8H) 0.76-0.96 (m, 12H); MS (ESI) m/z 1063 (M+H)⁺.

Example 6.12methyl{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-[4-(6-azaspiro[2.5]oct-6-yl)-3,5-difluorophenyl]-5-{6-fluoro-2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-6-fluoro-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

In an oven-dried 5-mL pear-shaped flask, dissolved(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (56.6 mg, 0.323 mmol)in anhydrous CH₂Cl₂ (1 mL) under nitrogen, added EDAC (63.2 mg, 0.323mmol), and stirred at 20° C. for 20 min. The resulting solution wasadded via gas-tight syringe to a solution of(S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(6-azaspiro[2.5]octan-6-yl)phenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole)hydrochloride (91 mg) and diisopropylethylamine (0.188 mL, 1.077 mmol)in anhydrous CH₂Cl₂ (2 mL) under nitrogen, added HOBt hydrate (49.5 mg,0.323 mmol), and stirred at 20° C. for 1 hr. The reaction was dilutedwith CH₂Cl₂ (50 mL), washed with water (25 mL), dried over anhydrousNa₂SO₄, filtered, and concentrated by rotary evaporation to a darkyellow foam (˜140 mg). Dissolved 70 mg of the impure material in 2 mLAcetonitrile and 2 mL 0.1% TFA in H₂O, and purified by RP-C₁₈ HPLC(Waters Prep LC, 40 mm Module with Nova Pak HR C18 6 μm 40×100 mm PrepPak cartridge) eluting with a 30 min gradient of 95:5 0.1% TFA inH₂O/Acetonitrile to 25:75 0.1% TFA in H₂O/Acetonitrile, then 10 min to100% Acetonitrile at 20 mL/min. Pure fractions were treated withsaturated aqueous NaHCO₃ (2 mL/tube), vortexed each tube to thoroughlyneutralize TFA, and combined the solutions in a 500-mL round bottomflask. Purified the remaining 70 mg by prep-HPLC as above and the pureproduct-containing fractions were treated with saturated aqueous NaHCO₃as above and combined in the same 500-mL round bottom flask. Removed theAcetonitrile by rotary evaporation, extracted the remaining aqueousphase with EtOAc (2×50 mL), dried the combined organic extracts overanhydrous MgSO₄, filtered, and concentrated by rotary evaporation toafford the product as a white solid (49 mg, 0.048 mmol). ¹H NMR (400MHz, DMSO-d₆) δ ppm 0.24 (s, 4H), 0.68-0.91 (m, 12H), 1.21-1.35 (m, 5H),1.67-2.07 (m, 9H), 2.13-2.24 (m, 4H), 2.84 (s, 4H), 3.53 (s, 6H),3.73-3.87 (m, 4H), 3.99-4.11 (m, 2H), 5.02-5.23 (m, 2H), 5.45-5.65 (m,2H), 5.81-5.99 (m, 2H), 7.04 (d, J=6.07 Hz, 1H), 7.14 (d, J=6.94 Hz,1H), 7.26-7.36 (m, 3H), 7.41 (dd, J=11.06, 6.18 Hz, 1H), 11.73-12.63 (m,2H); MS (ESI+) m/z 1013 (M+H)⁺; MS (ESI−) m/z 1011 (M−H)⁻.

Example 6.13methyl{(2S,3R)-1-[(2S)-2-{5-[(2R,5R)-1-[4-(4-tert-butylpiperidin-1-yl)-3,5-difluorophenyl]-5-(6-fluoro-2-{(2S)-1-[N-(methoxycarbonyl)-O-methyl-L-threonyl]pyrrolidin-2-yl}-1H-benzimidazol-5-yl)pyrrolidin-2-yl]-6-fluoro-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methoxy-1-oxobutan-2-yl}carbamate

(2S,3R)-3-Methoxy-2-(methoxycarbonylamino)butanoic acid (65.6 mg, 0.343mmol) was dissolved in anhydrous CH₂Cl₂ (1 mL) under nitrogen. EDAC(67.1 mg, 0.343 mmol) was added, and the mixture was stirred at 20° C.for 20 minutes. The resulting solution was added via to a solution of(S)-6,6′-((2R,5R)-1-(4-(4-tert-butylpiperidin-1-yl)-3,5-difluorophenyl)pyrrolfluoro-2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole) hydrochloride (100mg) and diisopropylamine (0.200 mL, 1.143 mmol) in anhydrous CH₂Cl₂ (2mL) under nitrogen. HOBt hydrate (52.5 mg, 0.343 mmol) was added, andthe mixture was stirred at 20° C. for 1 hour. The reaction was dilutedwith CH₂Cl₂ (50 mL), washed with water (25 mL), dried over anhydrousNa₂SO₄, filtered, and concentrated by rotary evaporation to a darkyellow foam (140 mg). The crude material (70 mg) was dissolved inacetonitrile (2 mL) and 0.1% TFA in H₂O (2 mL), and purified by RP-C₁₈HPLC (Waters Prep LC, 40 mm module with Nova-Pak® HR C18 6 μm 40×100 mmPrep Pak cartridge) eluting with a 30 minute gradient of 95:5 0.1% TFAin H₂O/acetonitrile to 25:75 0.1% TFA in H₂O/acetonitrile, then 10minutes to 100% acetonitrile at 20 mL/minute. Pure fractions weretreated with saturated aqueous NaHCO₃ (2 mL/tube), each tube wasvortexed to thoroughly neutralize TFA, and the fractions were combinedin a 500-mL round bottom flask. The remaining 70 mg of material waspurified by prep-HPLC as described above and the pure product-containingfractions were treated with saturated aqueous NaHCO₃ as above andcombined in the same 500-mL round bottom flask. The acetonitrile wasremoved by rotary evaporation, the remaining aqueous phase was extractedwith EtOAc (2×50 mL), the combined organic extracts were dried overanhydrous MgSO₄, filtered, and concentrated by rotary evaporation toafford the product as a white solid (62 mg, 0.057 mmol). ¹H NMR (400MHz, DMSO-d₆) δ ppm 0.80 (s, 9H), 0.92 (d, J=6.07 Hz, 2H), 0.98-1.09 (m,4H), 1.12-1.22 (m, 2H), 1.44-1.63 (m, 3H), 1.65-1.89 (m, 3H), 1.91-2.10(m, 4H), 2.11-2.28 (m, 4H), 2.73-2.92 (m, 4H), 3.04 (d, J=1.73 Hz, 2H),3.13 (s, 3H), 3.25 (d, J=3.47 Hz, 1H), 3.41-3.50 (m, 3H), 3.53 (s, 6H),3.72-3.92 (m, 4H), 4.25 (q, J=7.99 Hz, 2H), 5.02-5.17 (m, 2H), 5.46-5.63(m, 2H), 5.79-6.00 (m, 2H), 7.02 (d, J=6.72 Hz, 1H), 7.08-7.18 (m, 2H),7.24 (d, J=8.02 Hz, 1H), 7.33 (dd, J=10.36, 4.50 Hz, 1H), 7.40 (dd,J=11.22, 6.23 Hz, 1H), 11.84-12.63 (m, 2H); MS (ESI+) m/z 1075 (M+H)⁺;MS (ESI−) m/z 1073 (M−H)⁻.

Example 6.14dimethyl({(2R,5R)-1-[4-(4-tert-butylpiperidin-1-yl)-3,5-difluorophenyl]pyrrolidine-2,5-diyl}bis{(6-fluoro-1H-benzimidazole-5,2-diyl)(2S)pyrrolidine-2,1-diyl[(1S)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethane-2,1-diyl]})biscarbamate

(S)-2-(Methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid(74.5 mg, 0.343 mmol) was dissolved in anhydrous CH₂Cl₂ (1 mL) undernitrogen. EDAC (67.1 mg, 0.343 mmol) was added, and the mixture wasstirred at 20° C. for 20 minutes. The resulting solution was added to asolution of(S)-6,6′-((2R,5R)-1-(4-(4-tert-butylpiperidin-1-yl)-3,5-difluorophenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-2((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole)hydrochloride (100 mg) and diisopropylethylamine (0.200 mL, 1.143 mmol)in anhydrous CH₂Cl₂ (2 mL) under nitrogen. HOBt hydrate (52.5 mg, 0.343mmol) was added, and the mixture was stirred at 20° C. for 1 hour. Thereaction was diluted with CH₂Cl₂ (50 mL), washed with water (25 mL),dried over anhydrous Na₂SO₄, filtered, and concentrated by rotaryevaporation to a dark yellow solid (210 mg). The impure material (70 mg)was dissolved in 2 mL acetonitrile and 2 mL 0.1% TFA in H₂O, andpurified by RP-C₁₈ HPLC (Waters Prep LC, 40 mm module with Nova-Pak® HRC18 6 μm 40×100 mm Prep Pak cartridge) eluting with a 30 minute gradientof 95:5 0.1% TFA in H₂O/acetonitrile to 25:75 0.1% TFA inH₂O/acetonitrile, then 10 minutes to 100% acetonitrile at 20 mL/minute.Pure fractions were treated with saturated aqueous NaHCO₃ (2 mL/tube),each tube was vortexed to thoroughly neutralize TFA, and the fractionswere combined in a 500-mL round bottom flask. The remaining material waspurified in two 70 mg injections by prep-HPLC as described above, andthe pure product-containing fractions were treated with saturatedaqueous NaHCO₃ as above and combined in the same 500-mL round bottomflask. The acetonitrile was removed by rotary evaporation, the remainingaqueous phase was extracted with EtOAc (2×50 mL), the combined organicextracts were dried over anhydrous MgSO₄, filtered, and concentrated byrotary evaporation to afford the product as a white solid (69 mg, 0.060mmol). ¹H NMR (400 MHz, DMSO-d_(b)) δ ppm 0.80 (s, 9H), 0.89-1.01 (m, 1H), 1.07-1.38 (m, 7H), 1.39-1.63 (m, 6H), 1.67-1.91 (m, 5H), 1.92-2.05(m, 4H), 2.10-2.26 (m, 4H), 2.71-2.95 (m, 5H), 2.96-3.25 (m, 3H), 3.52(s, 6H), 3.62-3.92 (m, 8H), 4.06-4.23 (m, 2H), 5.10 (t, J=6.23 Hz, 2H),5.39-5.65 (m, 2H), 5.77-5.99 (m, 2H), 7.01 (d, J=6.72 Hz, 1H), 7.07 (d,J=7.05 Hz, 1H), 7.28-7.49 (m, 4H), 11.78-12.42 (m, 2H); MS (ESI+) m/z1127 (M+H)⁺; MS (ESI−) m/z 1125 (M−H)⁻.

Example 6.15methyl{(2S,3R)-1-[(2S)-2-{5-[(2R,5R)-1-(3,5-difluoro-4-{4-[4-(trifluoromethyl)phenyl]piperazin-1-yl}phenyl)-5-(6-fluoro-2-{(2S)-1-[N-(methoxycarbonyl)-O-methyl-L-threonyl]pyrrolidin-2-yl}-1H-benzimidazol-5-yl)pyrrolidin-2-yl]-6-fluoro-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methoxy-1-oxobutan-2-yl}carbamate

(S)-6,6′-((2R,5R)-1-(3,5-Difluoro-4-(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole)hydrochloride (88 mg),(2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid (41 mg, 0.216mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (46mg, 0.238 mmol), 1-hydroxybenzotriazole hydrate (36 mg, 0.238 mmol) and4-methylmorpholine (0.095 mL, 0.864 mmol) were dissolved in DMF (3.0mL), and the mixture stirred at room temperature for 3 hours.Afterwards, an isopropyl alcohol and chloroform mixture was added thenextracted with 1 N aqueous hydrochloric acid. The organic extract wasdried, filtered and concentrated, and then the residue was purified bychromatography (silica gel, methanol in dichloromethane) which afforded71 mg of the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.56 (m,2H), 7.48 (d, J=8.8 Hz, 2H), 7.34 (m, 2H), 7.18 (m, 2H), 7.04 (d, J=8.6Hz, 2H), 5.97 (m, 2H), 5.62 (m, 2H), 5.17 (m, 2H), 4.28 (m, 2H), 3.82(m, 2H), 3.60 (m, 2H), 3.54 (s, 6H), 3.25 (m, 8H), 3.17 (s, 6H), 2.99(m, 4H), 2.05 (m, 12H), 1.25 (m, 6H); MS (ESI) m/z 1164 (M+H)⁺.

Example 6.16methyl{(2S)-1-[(2S)-2-{6-[(2R,5R)-1-{4-[4-(2,6-difluorophenyl)piperazin-1-yl]-3,5-difluorophenyl}-5-{5-fluoro-2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-6-yl}pyrrolidin-2-yl]-5-fluoro-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

(S)-2-(Methoxycarbonylamino)-3-methylbutanoic acid (0.072 g, 0.410mmole) and HOBt (0.063 g, 0.410 mmole) were combined in DMF (2 mL). Tothe clear solution was added EDAC (0.079 g, 0.410 mmole) with a 0.2 mlDMF rinse, and the resulting clear solution was stirred at roomtemperature for 20 minutes.(S)-6,6′-((2R,5R)-1-(4-(4-(2,6-Difluorophenyl)piperazin-1-yl)-3,5-difluorophenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole)hydrochloride (0.160 g) was dissolved in 2 ml DMF, treated withN-methylmorpholine (1.863 mmol, 0.205 ml), and then treated with theactivated amino acid solution and the resulting clear brown solution wasstirred at room temperature for 1 hour. The pH of the solution wasmeasured to be 8 by pH paper. Reaction progress was determined by LC-MSat 1 hour and analysis deemed reaction complete. The reaction mixturewas concentrated in vacuo to a brown mobile oil. The oil was dilutedwith 50 ml EtOAc and washed with 30 mL 10% NaHCO₃. The layers wereseparated and the aqueous layer was extracted with another 50 mL EtOAc.The combined organic extracts were washed with 10% NaCl, dried overanhydrous Na₂SO₄(s), filtered and solvent removed in vacuo leaving abrown oily residue. The residue was purified on a 12 g silica gel columneluted with a gradient of CH₂Cl₂/CH₃OH, 99/1 to 95/5 over 13 minutes,then 95/5 to 90/10 over 8 minutes. The fractions containing product werecombined and repurified on a 12 g gold column eluted with a gradient ofCH₂Cl₂/CH₃OH, 98/2 to 90/10 over 15 minutes. The fractions wereconcentrated in vacuo leaving a light brown solid as the title compound(50.3 mg). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.82 (m, 12H) 1.99 (m, 9H)2.18 (m, 2H) 2.95 (m, 4H) 3.05-3.17 (m, 5H) 3.53 (s, 6H) 3.79 (m, 4H)3.95-4.11 (m, 4H) 5.11 (m, 2H) 5.55 (m, 2H) 5.91 (m, 2H) 7.01 (m, 5H)7.29 (m, 4H) 12.14 (m, 2H); MS (ESI+) m/z 1100.3, (ESI−) m/z 1098.3(M−H)⁻.

Example 7.1methyl{(2S)-1-[(2S)-2-(4-{4-[2-(4-tert-butylphenyl)-1-(4-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-4-yl}phenyl)-1H-pyrrol-3-yl]phenyl)-1H-imidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

Example 7.1A 2-(4-bromophenylamino)-2-(4-tert-butylphenyl)acetonitrile

To a solution of 4-bromoaniline (10.0 g, 58.1 mmol) in THF (100 mL) wasadded 4-tert-butylbenzaldehyde (9.72 mL, 58.1 mmol), acetic acid (13.3mL, 233 mmol), potassium cyanide (3.79 g, 58.1 mmol) and water (50 mL).The resultant mixture was stirred at room temperature for 16 hours. Theresultant solid that formed was collected by vacuum filtration, washedwith hexane, and then dried to afford 15.3 g, (77%) of the titlecompound. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.49 (m, 4H), 7.37 (d, J=8.7 Hz,2H), 6.66 (d, J=8.8 Hz, 2H), 5.34 (d, J=8.1 Hz, 1H), 4.02 (d, J=8.0 Hz,1H), 1.34 (s, 9H).

Example 7.1B

(E)-3-(4-bromophenyl)prop-2-en-1-ol

To a solution of (E)-ethyl 3-(4-bromophenyl)acrylate (10.0 g, 39.2 mmol)in dichloromethane (151 mL) cooled to −78° C. was added a solution ofdiisobutylaluminum hydride (1.0 M in dichloromethane, 82 mL, 82 mmol)dropwise over 15 minutes time. The solution was then stirred for anadditional 2 hours followed by the addition of a solution of 10% aqueoussodium hydroxide (250 mL). The mixture was allowed to warm to roomtemperature, and then the mixture was extracted with dichloromethane.The organic layer was dried and concentrated to afford 8.35 g (100%) ofthe title compound used directly in the next reaction.

Example 7.1C (E)-3-(4-bromophenyl)acrylaldehyde

To the product of Example 7.1B (8.35 g, 39.2 mmol) dissolved indichloromethane (151 mL) was added pyridinium dichromate (22.11 g, 58.8mmol), and the resultant mixture was stirred for 16 hours at roomtemperature. A solution of hexane was added, and the resultant mixturefiltered through diatomaceous earth, and then concentrated. Water wasadded to the residue, and the mixture was extracted with ethyl acetate.The organic layers were combined, dried and then concentrated. Theresidue was purified by chromatography (silica gel, hexanes in ethylacetate) which afforded 5.5 g, (67%) of the title compound. ¹H NMR (400MHz, CDCl₃) δ ppm 9.62 (d, J=7.6 Hz, 1H), 7.57 (d, J=8.5 Hz, 2H), 7.42(m, 3H), 6.70 (dd, J=15.9, 7.6 Hz, 1H).

Example 7.1D 1,3-bis(4-bromophenyl)-2-(4-tert-butylphenyl)-1H-pyrrole

To the product of Example 7.1C (0.676 g, 3.2 mmol) and the product fromExample 7.1A (1.0 g, 2.91 mmol) was added ethanol (30 mL) followed bypotassium hydroxide (0.163 g, 2.91 mmol), and the mixture was stirred atroom temperature for 16 hours. Afterwards the mixture was concentrated.The residue was partitioned between water and ethyl acetate. The organiclayers were combined, dried and then concentrated. The residue waspurified by chromatography (silica gel, hexanes in ethyl acetate) whichafforded 150 mg, (10%) of the title compound. ¹H NMR (400 MHz, CDCl₃) δppm 7.37 (m, 3H), 7.32 (d, J=8.5, 2H), 7.21 (d, J=8.4 Hz, 2H), 7.06 (d,J=8.3 Hz, 2H), 6.93 (m, 4H), 6.51 (dd, J=2.9 Hz, 1H), 1.29 (s, 9H).

Example 7.1E2-(4-tert-butylphenyl)-1,3-bis(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrrole

A solution of the product from Example 7.1D (150 mg, 0.295 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (165 mg,0.648 mmol), potassium acetate (87 mg, 8.84 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (21.6 mg, 0.029 mmol) in dioxane (5.5 mL) washeated at 100° C. for 18 hours. The mixture was then filtered throughdiatomaceous earth and concentrated to an oil which was dissolved inEtOAc and extracted with brine. The organic extract was concentrated toafford 230 mg of the title compound that was used directly in the nextstep.

Example 7.1F

di-tert-butyl(2S,2′S)-2,2′-{[2-(4-tert-butylphenyl)-1H-pyrrole-1,3-diyl]bis(benzene-4,1-diyl-1H-imidazole-4,2-diyl)}dipyrrolidine-1-carboxylate(ACD Name v12)

The product from Example 7.1E (227 mg, 0.376 mmol), (S)-tert-butyl2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate or (S)-tert-butyl2-(4-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (357 mg, 1.13mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II),complex with dichloromethane (27.5 mg, 0.038 mmol), and a solution ofsodium carbonate (1.0 M in water, 1.13 mL, 1.13 mmol) were heated in asolution of ethanol (3 mL) and toluene (3 mL) at 85° C. for 18 hours.The mixture then had water (10 mL) added followed by extraction withEtOAc (2×10 mL). The organic extract was dried, filtered andconcentrated, and then the residue was purified by chromatography(silica gel, methanol in dichloromethane) which afforded 29 mg, (9%) ofthe title compound; MS (ESI) m/z 823 (M+H)⁺.

Example 7.1G4,4′-{[2-(4-tert-bury(phenyl)-1H-pyrrole-1,3-diyl]dibenzene-4,1-diyl}bis(2-[(2S)-pyrrolidin-2-yl]-1H-imidazole)(ACD Name v12)

The product of Example 7.1F (29 mg, 0.035 mmol) was dissolved in dioxane(0.5 mL) and hydrochloric acid in dioxane (4.0 N, 0.14 mL, 0.54 mmol)was added. The mixture was stirred at room temperature for 4 hours.Afterwards the mixture was concentrated to afford the title compound asa hydrochloride salt. MS (ESI) m/z 622 (M+H)⁺.

Example 7.1Hmethyl{(2S)-1-[(2S)-2-(4-{4-[2-(4-tert-butylphenyl)-1-(4-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-4-yl)phenyl)-1H-pyrrol-3-yl]phenyl}-1H-imidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

The product from Example 7.1G (22 mg, 0.036 mmol),(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (12.7 mg, 0.072mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride(15.2 mg, 0.079 mmol), 1-hydroxybenzotriazole hydrate (12.2 mg, 0.079mmol) and 4-methylmorpholine (0.021 mL, 0.29 mmol) were dissolved in DMF(0.7 mL), and the mixture was stirred at room temperature for 3 hours.Afterwards, 1 N aqueous hydrochloric acid (5 mL) was added followed byextraction with dichloromethane (2×5 mL). The organic extract was dried,filtered and concentrated. Then the residue was purified bychromatography (silica gel, methanol in dichloromethane) which afforded3.3 mg, (10%) of the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm10.57 (s, 1H), 10.26 (s, 1H), 7.62 (m, 4H), 7.20 (m, 8H), 6.99 (m, 4H),5.37 (m, 2H), 5.24 (m, 2H), 4.30 (m, 2H), 3.80 (m, 2H), 3.08 (m, 1H),2.96 (s, 3H), 2.88 (s, 3H), 2.30 (m, 2H), 2.19 (m, 2H), 2.08 (m, 2H),1.92 (m, 2H), 1.23 (m, 9H), 0.85 (m, 12H); MS (ESI) m/z 936 (M+H)⁺.

Example 8dimethyl({(2S)-[3,5-difluoro-4-(4-phenylpiperidin-1-yl)phenyl]pyrrolidine-2,5-diyl}bis{4,1-phenylenecarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-1-oxobutane-1,2-diyl]})biscarbamate

Example 8A1-(4-((2S,5S)-2,5-bis(4-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-4-phenylpiperidine

A mixture of Intermediate 6 (2.68 g, 5.49 mmol),3,5-difluoro-4-(4-phenylpiperidin-1-yl)aniline (1.90 g, 6.58 mmol) anddiisopropylethylamine (9.58 mL, 54.9 mmol) in DMF (18.3 mL) was heatedat 60° C. for 18 hours. Afterwards ethyl acetate was added to thesolution followed by extraction with water. The organic extract wasdried, filtered and concentrated then the residue purified bychromatography (silica gel, ethyl acetate in hexanes) which afforded 197mg, (6%) of the title compound. MS (ESI) m/z 585 (M+H)⁺.

Example 8B4,4′-((2S,5S)-1-(3,5-difluoro-4-(4-phenylpiperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)dianiline

The product of Example 8A (197 mg, 0.337 mmol) was dissolved in amixture of THF (3 mL), ethanol (3 mL) and water (0.5 mL), and then iron(95 mg, 1.69 mmol) and ammonium chloride (27 mg, 0.506 mmol) were addedand the mixture heated at 80° C. for 3 hours. Afterwards ethyl acetatewas added to the solution followed by extraction with sodiumbicarbonate. The organic extract was dried, filtered and concentratedwhich afforded 177 mg (100%) of the title compound. MS (ESI) m/z 525(M+H)⁺.

Example 8C (2S,2′S)-tert-butyl2,2′-(4,4′-((2S,5S)-1-(3,5-difluoro-4-(4-phenylpiperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-1-carboxylate

The product from Example 8B (177 mg, 0.337 mmol), (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (160 mg, 0.742 mmol),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (162 mg,0.843 mmol), 1-hydroxybenzotriazole hydrate (129 mg, 0.843 mmol) and4-methylmorpholine (0.370 mL, 3.37 mmol) were dissolved indichloromethane (3.5 mL), and the mixture stirred at room temperaturefor 19 hours. Afterwards, aqueous sodium bicarbonate was added followedby extraction with dichloromethane. The organic extract was dried,filtered and concentrated, and then the residue was purified bychromatography (silica gel, methanol in dichloromethane) which afforded130 mg, (42%) of the title compound. MS (ESI) m/z 920 (M+H)⁺.

Example 8D(2S,2′S)—N,N′—(4,4′-((2S,5S)-1-(3,5-difluoro-4-(4-phenylpiperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(4,1-phenylene))dipyrrolidine-2-carboxamide

The product of Example 8C (130 mg, 0.141 mmol) was dissolved indichloromethane (2.7 mL) and trifluoroacetic acid (0.27 mL, 3.5 mmol)and the mixture was stirred at room temperature for 1 hour. Afterwardsthe mixture was concentrated, the residue was dissolved in an isopropylalcohol and chloroform mixture and then extracted with aqueous sodiumbicarbonate. The organic phase was then dried and concentrated to afford100 mg (99%) of the title compound. MS (ESI) m/z 719 (M+H)⁺.

Example 8Edimethyl({(2S)-1-[3,5-difluoro-4-(4-phenylpiperidin-1-yl)phenyl]pyrrolidine-2,5-diyl}bis{4,1-phenylenecarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-1-oxobutane-1,2-diyl]})biscarbamate

The product from Example 8D (100 mg, 0.142 mmol),(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (60 mg, 0.341 mmol),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (68 mg,0.355 mmol), 1-hydroxybenzotriazole hydrate (54 mg, 0.355 mmol) and4-methylmorpholine (0.156 mL, 1.42 mmol) were dissolved in DMF (1.5 mL),and the mixture was stirred at room temperature for 19 hours.Afterwards, an isopropyl alcohol and chloroform mixture was added andthen extracted with aqueous sodium bicarbonate. The organic extract wasdried, filtered and concentrated, and then the residue was purified bychromatography (silica gel, methanol in dichloromethane) which afforded20 mg, (14%) of the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm10.03 (s, 2H), 7.53 (d, J=8.5 Hz, 4H), 7.30 (m, 9H), 5.83 (d, J=12.6 Hz,2H), 5.18 (m, 2H), 5.08 (m, 2H), 4.43 (m, 2H), 4.02 (m, 4H), 3.61 (m,2H), 3.54 (s, 6H), 2.98 (m, 4H), 2.18 (m, 2H), 1.93 (m, 6H), 1.70 (m,6H), 0.81 (m, 12H); MS (ESI) m/z 1033 (M+H)⁺.

Example 9methyl{(2S)-1-[(2S)-2-(4-{4-[(2R,5R)-1-[3,5-difluoro-4-(4-phenylpiperidin-1-yl)phenyl]-5-(4-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-4-yl}phenyl)pyrrolidin-2-yl]phenyl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

Example 9A1-(4-((2R,5R)-2,5-bis(4-bromophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-4-phenylpiperidine

A mixture of Intermediate 7 (2.35 g, 4.22 mmol),3,5-difluoro-4-(4-phenylpiperidin-1-yl)aniline (2.44 g, 8.45 mmol) anddiisopropylethylamine (2.21 mL, 12.67 mmol) in acetonitrile (25 mL) washeated at 80° C. for 9 hours. Afterwards the resultant solid was removedby filtration and purified by chromatography (silica gel, hexanes inethyl acetate then dichloromethane in hexanes) which afforded 130 mg,(4.7%) of the title compound. MS (ESI+) m/z 653 (M+H)⁺.

Example 9B1-(4-((2R,5R)-2,5-bis(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-4-phenylpiperidine

A solution of the product from Example 9A (130 mg, 0.199 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (121 mg,0.478 mmol), potassium acetate (59 mg, 0.598 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (29 mg, 0.04mmol) in dioxane (4.5 mL) was heated at 100° C. for 3 hours. The mixturewas then filtered through diatomaceous earth and concentrated to an oilwhich was dissolved in EtOAc and extracted with 1 N aqueous hydrochloricacid. The organic extract was dried, filtered and concentrated, and thenthe residue was purified by chromatography (silica gel, ethyl acetate inhexanes) which afforded 50 mg, (34%) of the title compound. MS (ESI) m/z747 (M+H)⁺.

Example 9C (2S,2′S)-tert-butyl2,2′-(4,4′-(4,4′-((2R,5R)-1-(3,5-difluoro-4-(4-phenylpiperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(4,1-phenylene))bis(1H-imidazole-4,2-diyl))dipyrrolidine-1-carboxylate

The product from Example 9B (50 mg, 0.067 mmol), Intermediate 1 (64 mg,0.201 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)(6.1 mg, 0.0084 mmol), and sodium carbonate (1.0 M in water, 0.27 mL,0.27 mmol) were heated in ethanol (1.5 mL) and toluene (1.5 mL) at 85°C. for 17 hours. Water (10 mL) was added to the mixture followed byextraction with dichloromethane. The organic extract was dried, filteredand concentrated, and then the residue was purified by chromatography(silica gel, methanol in dichloromethane) which afforded 51 mg, (79%) ofthe title compound. MS (ESI) m/z 966 (M+H)⁺.

Example 9D1-(4-((2R,5R)-2,5-bis(4-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-4-yl)phenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-4-phenylpiperidine

The product of Example 9C (50 mg, 0.052 mmol) was dissolved in dioxane(1.5 mL) and hydrochloric acid in dioxane (4.0 N, 0.65 mL, 2.6 mmol),and the mixture was stirred at room temperature for 4 hours. Afterwardsthe mixture was concentrated to afford the title compound as ahydrochloride salt. MS (ESI) m/z 765 (M+H)⁺.

Example 9Emethyl{(2S)-1-[(2S)-2-(4-{4-[(2R,5R)-1-[3,5-difluoro-4-(4-phenylpiperidin-1-yl)phenyl]-5-(4-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-4-yl}phenyl)pyrrolidin-2-yl]phenyl)-1H-imidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

The product from Example 9D (40 mg, 0.052 mmol),(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (18.3 mg, 0.105mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride(22.1 mg, 0.115 mmol), 1-hydroxybenzotriazole hydrate (17.6 mg, 0.115mmol) and 4-methylmorpholine (0.046 mL, 0.418 mmol) were dissolved inDMF (1.5 mL), and the mixture was stirred at room temperature for 19hours. Afterwards, 1 N aqueous hydrochloric acid was added followed byextraction with dichloromethane. The organic extract was dried, filteredand concentrated, and then the residue was purified by chromatography(silica gel, methanol in dichloromethane) which afforded 25 mg, (44%) ofthe title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.64 (m, 5H), 7.23(m, 11H), 5.89 (d, J=12.8 Hz, 2H), 5.23 (m, 2H), 5.08 (m, 2H), 4.06 (m,2H), 3.80 (m, 4H), 3.53 (s, 6H), 2.96 (m, 4H), 2.18 (m, 2H), 1.99 (m,6H), 1.70 (m, 6H), 0.83 (m, 12H); MS (ESI) m/z 1080 (M+H)⁺.

From the product of General Procedure 11C, the compounds of Examples10.1 and 10.2 can be obtained by the steps of: (1) coupling with(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid; (2) removal of thesingle Boc protecting group; and (3) coupling with a second selectedcarbamate-protected amino acid.

Example 10.1methyl[(1S)-2-[(2S,3aS,6aS)-2-{5-[(2R,5R)-1-[3,5-difluoro-4-(piperidin-1-yl)phenyl]-5-{2-[(2S,3aS,6aS)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}octahydrocyclopenta[b]pyrrol-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}hexahydrocyclopenta[b]pyrrol-1(2H)-yl]-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl]carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.70-0.91 (m, 6H) 1.10-1.27 (m, 2H)1.34-1.49 (m, 8H) 1.50-1.64 (m, 4H) 1.65-1.81 (m, 4H) 1.84-2.03 (m, 6H)2.05-2.18 (m, 4H) 2.36-2.46 (m, 4H) 2.72-2.86 (m, 6H) 3.02-3.21 (m, 2H)3.54 (s, 6H) 3.70-3.89 (m, 2H) 3.97-4.17 (m, 2H) 4.72-4.86 (m, 2H)5.07-5.20 (m, 2H) 5.32-5.43 (m, 2H) 5.84-5.94 (m, 2H) 7.07 (t, J=10.08Hz, 2H) 7.17-7.27 (m, 2H) 7.30-7.56 (m, 4H) 11.92-11.99 (m, 1H)12.03-12.13 (m, 1H); MS (ESI+) m/z 1073.4 (M+H)⁺.

Example 10.2methyl{(2S,3R)-1-[(2S,3aS,6aS)-2-{5-[(2R,5R)-1-[3,5-difluoro-4-(piperidin-1-yl)phenyl]-5-{2-[(2S,3aS,6aS)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}octahydrocyclopenta[b]pyrrol-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}hexahydrocyclopenta[b]pyrrol-1(2H)-yl]-3-methoxy-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.70-0.89 (m, 6H) 0.99 (ddd, J=34.43,6.29, 3.31 Hz, 3H) 1.35-1.48 (m, 6H) 1.50-1.63 (m, 4H) 1.66-1.80 (m, 6H)1.83-2.00 (m, 6H) 2.05-2.16 (m, 4H) 2.72-2.83 (m, 4H) 3.17 (s, 3H)3.21-3.28 (m, 4H) 3.54 (s, 6H) 4.02 (t, J=7.48 Hz, 1H) 4.20-4.30 (m, 1H)4.80 (t, J=7.97 Hz, 2H) 5.08-5.17 (m, 2H) 5.32-5.43 (m, 2H) 5.83-5.94(m, 2H) 7.05 (dd, J=8.24, 1.30 Hz, 2H) 7.21 (s, 1H) 7:30 (d, J=3.14 Hz,1H) 7.40 (d, J=7.92 Hz, 1H) 7.45-7.56 (m, 3H) 11.99 (dd, J=9.87, 1.63Hz, 1H) 12.04-12.13 (m, 1H); MS (ESI+) m/z 1047.5 (M+H)⁺.

From the product of General Procedure 8B, Example 1B(mono-displacement), the compounds of Examples 11.1 and 11.2 can beobtained by the steps of: (1) Buchwald reaction with an appropriatesecond amide (see General Procedure 8); (2) nitro reduction (see GeneralProcedure 9); and (3) cyclization (see General Procedure 10).

Example 11.1methyl[(1S)-2-[(2S)-2-{5-[(2R,5R)-1-[3,5-difluoro-4-(4-phenylpiperidin-1-yl)phenyl]-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl]carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.74-0.91 (m, 6H) 1.44-1.56 (m, 2H)1.62-1.75 (m, 6H) 1.82-1.95 (m, 2H) 1.97-2.07 (m, 4H) 2.16-2.26 (m, 4H)2.87-3.16 (m, 7H) 3.43-3.50 (m, 2H) 3.53 (s, 6H) 3.58-3.66 (m, 2H)3.70-3.78 (m, 2H) 3.80-3.89 (m, 4H) 4.06 (t, J=8.51 Hz, 2H) 5.11-5.19(m, 2H) 5.33-5.43 (m, 2H) 5.86-5.95 (m, 2H) 7.06-7.11 (m, 2H) 7.12-7.37(m, 9H) 7.42 (dd, J=7.92, 1.73 Hz, 1H) 7.46-7.53 (m, 1H) 12.04-12.20 (m,2H); MS (ESI+) m/z 1069.4 (M+H)⁺.

Example 11.2methyl{(2S)-1-[(2S)-2-(5-{(2R,5R)-5-(2-cyclopentyl-1H-benzimidazol-5-yl)-1-[3,5-difluoro-4-(4-phenylpiperidin-1-yl)phenyl]pyrrolidin-2-yl}-1H-benzimidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.76-0.91 (m, 6H) 1.59-1.73 (m, 10H)1.73-1.80 (m, 2H) 1.83-1.94 (m, 4H) 1.97-2.08 (m, 4H) 2.16-2.24 (m, 1H)2.86-3.04 (m, 6H) 3.19-3.29 (m, 1H) 3.53 (s, 3H) 3.79-3.87 (m, 2H)5.11-5.19 (m, 1H) 5.34-5.42 (m, 2H) 5.88-5.95 (m, 2H) 7.03-7.11 (m, 2H)7.13-7.19 (m, 2H) 7.20-7.27 (m, 4H) 7.28-7.34 (m, 2H) 7.40 (dd, J=13.88,8.24

Hz, 1H) 7.50 (d, J=8.02 Hz, 1H) 12.05 (d, J=10.63 Hz, 1H) 12.12 (d,J=3.90 Hz, 1H); MS (ESI+) m/z 869.4 (M+H)⁺.

Example 12.1methyl{(2S)-1-[(2S)-2-(5-{3-[1-(4-tert-butylphenyl)-3-(3-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-5-yl}phenyl)azetidin-3-yl]phenyl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamateExample 12.1A bis(3-bromophenyl)methanol

n-Bui (26.5 mL, 42.4 mmol, 1.6M in hexane) was added to a solution of1,3-dibromobenzene (10 g, 42.4 mmol) in THF (50 mL) at −78° C. Afterstirred for 2 h at −78° C., the 3-bromobenzaldehyde (7.84 g, 42.4 mmol)was added to the reaction mixture. The reaction mixture was allowed towarm up to r.t. and stirred at 30° C. for 12 h. The reaction wasquenched with aq NH₄Cl (100 mL). The mixture was extracted withdichloromethane (80 mL×5). The combined organic layers were dried andconcentrated. The residue was purified by column chromatography (onsilica gel, eluent with Petroleum ether ˜Petroleum ether: EtOAc=20:1) toafford 8.4 g of the title compound (24.5 mmol, 58%). LC/MS:[M−18+1]=325. ¹HNMR (DMSO-d₆), 400 MHz: δ 5.74 (d, 1H, J=4.0 Hz), 6.19(d, 1H, J=4.4 Hz), 7.26-7.31 (m, 2H), 7.37-7.43 (m, 4H), 7.59 (s, 2H).

Example 12.1B bis(3-bromophenyl)methanone

MnO₂ (21.61 g, 249 mmol) was added to a solution ofbis(3-bromophenyl)methanol (8.4 g, 24.5 mmol) in dichloromethane (80mL). The mixture was stirred at 25° C. for 12 h and then filtered. Thefilter cake was washed with dichloromethane (60 mL×5). The filtrate wasconcentrated to afford 7.6 g of the title compound (22.3 mmol, 90%).LC/MS: [M+1]=341. ¹H NMR (DMSO-d₆), 400 MHz: δ 7.52-7.56 (m, 2H), 7.71(d, 2H, J=7.2 Hz), 7.88-7.92 (m, 4H).

Example 12.1C 2,2-bis(3-bromophenyl)oxirane

KOt-Bu (2.72 g, 24.26 mmol) was added to a stirred suspension ofbis(3-bromophenyl)methanone (7.5 g, 22.06 mmol) and trimethylsulfoniumiodide (4.50 g, 22.06 mmol) in DMSO (20 mL) and the resulting mixturewas stirred at 30° C. for 8 h. The mixture was diluted with ethylacetate (500 mL), washed with water (500 mL×3) and brine (500 mL). Theorganic layer was separated and evaporated in vacuo to afford the titlecompound which was used directly without further purification.

Example 12.1D 2,2-bis(3-bromophenyl)propane-1,3-diol

A mixture of the crude 2,2-bis(3-bromophenyl)oxirane (7.4 g, 20.90 mmol)and p-toluenesulfonic acid monohydrate (360 mg, 2.1 mmol) in toluene (25mL) was stirred at 95° C. for 1 h. The solution was washed with aqNaHCO₃ (10 mL) and water (20 mL). The organic layer was dried andconcentrated. The residue was dissolved in EtOH (20 mL). To the solutionwas added formaldehyde (15.56 mL, 209 mmol, 37% aqueous solution) andK₂CO₃ (1.44 g, 10.45 mmol). The mixture was stirred at 85° C. for 12 h.After cooling to room temperature, the reaction mixture was diluted withwater (50 mL) and extracted with dichloromethane (60 mL×4). The combinedorganic layers were dried and concentrated. The residue was purified bycolumn chromatography (on silica gel, eluent with Petroleumether˜Petroleum ether: EtOAc=2:1) to afford 4.6 g of2,2-bis(3-bromophenyl)propane-1,3-diol (11.9 mmol, 57% after two steps).LC/MS: [M−18+1]=368. ¹HNMR (CDCl₃), 400 MHz: δ 2.53 (brs, 2H), 2.41 (s,4H), 7.09-7.20 (m, 4H), 7.36-7.40 (m, 4H).

Example 12.1E 2,2-bis(3-bromophenyl)propane-1,3-diyl dimethanesulfonate

To a stirred solution of 2,2-bis(3-bromophenyl)propane-1,3-diol (6.0 g,15.54 mmol) in dichloromethane (50 mL) at 0° C. was addedmethanesulfonic chloride (27.1 g, 155 mmol) and Et₃N (17.3 mL, 124 mmol)to give an orange solution. The reaction mixture was stirred at 0° C.for 1 h, then at 40° C. for 8 h. The reaction was washed with aq. NH₄Cl(80 mL). The aqueous layer was extracted with dichloromethane (50 mL×3).The combined organic layers were dried and concentrated. The residue waspurified by chromatography (on silica gel column, Petroleum ether:EtOAc=2:1) to afford 3.2 g of the title compound (5.9 mmol, 38%). LC/MS:[M+18]=560. ¹HNMR (CDCl₃), 400 MHz: δ 2.93 (s, 6H), 4.49 (s, 4H),7.15-7.48 (m, 8H).

Example 12.1F 3-azido-2,2-bis(3-bromophenyl)propyl methanesulfonate

To a solution of 2,2-bis(3-bromophenyl)propane-1,3-diyldimethanesulfonate (3.6 g, 6.64 mmol) in DMPU (25 mL, 207 mmol) under N₂was added NaN₃ (0.52 g, 7.97 mmol) with stirring. The mixture was heatedto 110° C. for 5 h. After cooling to room temperature, the reactionmixture was diluted with EtOAc (100 mL), and washed with water (30 mL×2)and brine (25 mL), dried and concentrated. The residue was purified bycolumn chromatography (on silica gel, eluent with Petroleum ether:EtOAc=3:1) to afford 1.3 g of the title compound (2.66 mmol, 40%).LC/MS: [M+18]=507. ¹HNMR (CDCl₃), 400 MHz: δ 2.83 (s, 3H), 4.07 (s, 2H),4.77 (s, 2H), 7.07-7.09 (m, 2H), 7.21-7.31 (m, 4H), 7.44-7.46 (m, 2H).

Example 12.1G diethyl 3,3-bis(3-bromophenyl)azetidin-1-ylphosphonate

To a solution of 3-azido-2,2-bis(3-bromophenyl)propyl methanesulfonate(1.3 g, 2.66 mmol) in anhydrous toluene (10 mL) and anhydrous THF (5 mL)under N₂ was added triethyl phosphite (0.49 mL, 2.79 mmol) at 25° C. Themixture was stirred for 18 h. The reaction was concentrated by rotaryevaporation in a dried apparatus. The residue was dried in vacuo, andused in the next reaction without further purification. The crudetriethyl phosphorimidate was dissolved in anhydrous m-xylene (5 mL)under N₂ and heated in an oil bath at 150° C. for 12 h. After cooled toroom temperature, the solvent was removed by rotary evaporation (vacuumpump assisted) to give a thick light orange oil which was purified byprep-TLC (eluent with EtOAc: dichloromethane=1:5) to afford 960 mg ofdiethyl 3,3-bis(3-bromophenyl)azetidin-1-ylphosphonate (1.9 mmol, 71%after two steps). LC/MS: [M+1]=504. ¹HNMR (CDCl₃), 400 MHz: δ 1.25-1.36(m, 6H), 4.05-4.39 (m, 4H), 4.40 (d, 2H, J=5.2

Hz), 7.09-7.11 (m, 2H), 7.20-7.27 (m, 2H), 7.40-7.42 (m, 4H).

Example 12.1H 3,3-bis(3-bromophenyl)azetidine

To a solution of diethyl 3,3-bis(3-bromophenyl)azetidin-1-ylphosphonate(960 mg, 1.9 mmol) in anhydrous dichloromethane (5 mL) under N₂ wasadded TFA (5 mL). The mixture was stirred at 20° C. for 3 h, thenconcentrated by rotary evaporation. The residue was dissolved indichloromethane (20 mL) and washed with aq. NaHCO₃ (30 mL). The organiclayer was dried and concentrated to afford 595 mg of the title compound(1.6 mmol, 85%) as a yellow oil which was used directly to next stepwithout purification. LC/MS: [M+1]=368.

Example 12.11 3,3-bis(3-bromophenyl)-1-(4-tert-butylphenyl)azetidine

A mixture of 3,3-bis(3-bromophenyl)azetidine (60 mg, 0.163 mmol),1-tert-butyl-4-iodobenzene (85 mg, 0.327 mmol), xantphos (9.46 mg, 0.016mmol), Pd₂(dba)₃ (3.74 mg, 4.09 μmol) and tert-butoxide (18.85 mg, 0.196mmol) in dioxane (5 mL) was stirred at 110° C. for 12 h. After thereaction was cooled to room temperature, water (15 mL) anddichloromethane (15 mL) was added. The aqueous phase was extracted withdichloromethane (15 mL×3). The combined organic layers were dried andconcentrated. The residue was purified by prep-HPLC (Instrument waters2767 PHW004 Column YMC-Triart C18 150*20 mm S-5 um 12 nm Mobile Phase A:water (0.05% NH₄HCO₃) B: ACN Gradient 95-95% B in 8 min stop in 14 minFlow Rate(ml/min) 20.00 Detective Wavalength(nm) 214\254 RetentionTime(min) 7.4 to afford 26 mg of the title compound (0.052 mmol, 31.8%yield). LC/MS: [M+1]=500.

Example 12.1J1-(4-tert-butylphenyl)-3,3-bis(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)azetidine

A mixture of 3,3-bis(3-bromophenyl)-1-(4-tert-butylphenyl)azetidine (50mg, 0.100 mmol), bis(pinacolato)diboron (65.9 mg, 0.260 mmol), KOAc(58.8 mg, 0.599 mmol) and PdCl₂(dppf)-CH₂Cl₂ adduct (20.39 mg, 0.025mmol) was stirred at 100° C. for 2 h under N₂. After cooling to roomtemperature, water (15 mL) and dichloromethane (15 mL) was added. Theaqueous layer was extracted with dichloromethane (15 mL×3). The combinedorganic layers were dried and concentrated. The residue was purified byprep-TLC (eluent with dichloromethane: hexane=1:1) to afford 50 mg ofthe title compound (0.078 mmol, 78% yield). LC/MS: [M−C₁₂H₂₀+1]=430;[M−C₆H₁₀+1]=512.

Example 12.1Kmethyl{(2S)-1-[(2S)-2-(5-{3-[1-(4-tert-butylphenyl)-3-(3-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-5-yl}phenyl)azetidin-3-yl]phenyl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

A mixture of1-(4-tert-butylphenyl)-3,3-bis(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)azetidine(50 mg, 0.084 mmol), Intermediate 4 (66.0 mg, 0.177 mmol),PdCl₂(dppf)-CH₂Cl₂ adduct (13.76 mg, 0.017 mmol) and K₂CO₃ (69.9 mg,0.506 mmol) in dioxane (5 mL) was stirred at 100° C. for 2 h. Aftercooling to room temperature, the reaction mixture was diluted withdichloromethane (20 mL) and washed with aq. NH₄Cl (15 mLl). The aqueouslayer was extracted with dichloromethane (15 mL×3), and the combinedorganic layers were washed with brine (25 mL), dried and concentrated.The residue was purified by prep-HPLC: Instrument waters 2767 PHW003Column Boston C18 10 um 21*250 mm Mobile Phase A:water(0.05% NH₄HCO₃);B:ACN Gradient 60-82% B in 8 min, stop at 14 min Flow Rate(ml/min) 30.00Detective Wavelength(nm) 214\254 Retention Time(min) 8.32. The puritywas 83% after first purification by prep-HPLC. The compound was furtherpurified by prep-TLC (eluent with MeOH: dichloromethane=1:15) to afford22 mg of the title compound (0.024 mmol, 28.2% yield). LC/MS: [M+1]=926.¹HNMR (MeOD-d₄), 400 MHz: δ 0.77-0.85 (m, 12H), 1.18 (s, 9H), 1.88-2.23(m, 10H), 3.07 (d, 2H, J=6.4 Hz), 3.56 (s, 6H), 3.75-3.89 (m, 4H),4.12-4.14 (m, 2H), 4.36-4.42 (m, 4H), 5.03-5.07 (m, 2H), 6.46-6.48 (m,2H), 6.73-6.77 (m, 1H), 7.10-7.23 (m, 9H), 7.39-7.41 (m, 2H), 7.68-7.72(m, 2H).

Example 12.2methyl{(2S)-1-[(2S)-2-(5-{3-[3-(3-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-5-yl}phenyl)-1-phenylazetidin-3-yl]phenyl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

Example 12.2A 3,3-bis(3-bromophenyl)-1-phenylazetidine

A mixture of 3,3-bis(3-bromophenyl)azetidine (200 mg, 0.545 mmol),iodobenzene (222 mg, 1.090 mmol), xantphos (31.5 mg, 0.054 mmol),Pd₂(dba)₃ (12.47 mg, 0.014 mmol) and sodium tert-butoxide (62.8 mg,0.654 mmol) in dioxane (3 ml) was stirred for 12 h at 100° C. Aftercooling to room temperature, water (15 mL) and dichloromethane (15 mL)was added. The aqueous layer was extracted with dichloromethane (15mL×3). The combined organic layers were dried and concentrated. Theresidue was purified by prep-TLC (eluent with dichloromethane:EtOAc=5:1) to afford 140 mg of the title compound (0.31 mmol, 58%).LC/MS: [M+1]=444, Ret. Time: 2.69 min. ¹HNMR (CDCl₃), 400 MHz: 4.42 (s,4H), 6.54 (d, 2H, J=7.6 Hz), 7.09-7.11 (m, 2H), 6.79 (t, 1H, J=7.2 Hz),7.17-7.26 (m, 6H), 7.37-7.45 (m, 4H).

Example 12.2B1-phenyl-3,3-bis(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)azetidine

A mixture of 3,3-bis(3-bromophenyl)-1-phenylazetidine (140 mg, 0.284mmol), KOAc (167 mg, 1.705 mmol), Pda₂(dppf)-CH₂Cl₂ adduct (58.0 mg,0.071 mmol) and bis(pinacolato)diboron (188 mg, 0.739 mmol) in dioxane(3 mL) was stirred at 110° C. for 2 h. After cooling to roomtemperature, the reaction mixture was diluted with dichloromethane (20mL) and washed with aq. NH₄O (15 mL). The aqueous layer was extractedwith dichloromethane (15 mL×3). The combined organic layers were washedwith brine (25 mL). The organic layers was dried and concentrated. Thecrude product was purified by prep-TLC (eluent with dichloromethane:Hexane=1:2) to afford 142 mg of the title compound (0.209 mmol, 73.6%yield). LC/MS: [M+1]=538.

Example 12.2Cmethyl{(2S)-1-[(2S)-2-(5-{3-[3-(3-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-5-yl}phenyl)-1-phenylazetidin-3-yl]phenyl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

A mixture of1-phenyl-3,3-bis(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)azetidine(60 mg, 0.112 mmol), Intermediate 4 (88 mg, 0.235 mmol),PdCl₂(dppf)-CH₂Cl₂ adduct (18.24 mg, 0.022 mmol) and K₂CO₃ (93 mg, 0.670mmol) in dioxane (5 mL) and water (1 mL) was stirred at 100° C. for 2 hunder N₂. The reaction mixture was diluted with dichloromethane (20 mL)and washed with aq. NH₄Cl (15 mL). The aqueous phase was extracted withdichloromethane (15 mL×3). The combined organic layers was washed withbrine (25 mL). The organic layers was dried and concentrated. The crudeproduct was purified by prep-HPLC (Instrument waters 2767 PHW003 ColumnBoston C18 10 um 21*250 mm Mobile Phase A:water (0.05% NH4HCO3); B:ACNGradient 45-70% B in 8 min, stop at 14 min Flow Rate(ml/min) 30.00Detective Wavalength(nm) 214\254 Retention Time(min) 8.47. Then thecompound was further purified by prep-TLC (eluent withMeOH:dichloromethane=1:15) to afford 20 mg of the title compound (0.022mmol, 19.53% yield). LC/MS: [M+1]=870. ¹HNMR (MeOD-d₄), 400 MHz: δ0.86-0.97 (m, 12H), 1.97-2.33 (m, 10H), 3.07 (d, 2H, J=6.4 Hz), 3.66 (s,6H), 3.83-3.99 (m, 5H), 4.21-4.23 (m, 2H), 4.49-4.55 (m, 5H), 5.13-5.16(m, 2H), 6.61-6.63 (m, 2H), 6.73-6.77 (m, 1H), 7.19-7.58 (m, 12H),7.78-7.80 (m, 2H).

The present invention also contemplates pharmaceutically acceptablesalts of each title compound described in the above examples. All of theexamples disclosed in U.S. Patent Application Publication No.2010/0317568 and U.S. patent application Ser. Nos. 12/903,822 and12/964,027 are also incorporated herein by reference.

When tested using HCV 1b-Con1 replicon assays in the presence of 5% FBS,each title compound in 1.1, 1.3, 1.5, 1.6, 1.7, 1.8, 2.1, 2.2, 2.4, 2.5,2.6, 2.9, 2.10, 2.11, 2.12, 2.13, 2.14, 2.15, 2.16, 2.17, 3.1, 3.2, 3.4,3.5, 3.6, 3.7, 3.8, 3.11, 3.12, 3.13, 3.15, 3.17, 3.18, 3.19, 3.20,3.21, 3.22, 3.23, 3.24, 3.25, 3.26, 3.27, 3.28, 3.29, 3.30, 3.31, 3.32,3.33, 3.34, 3.35, 3.36, 3.37, 3.38, 3.39, 3.40, 3.41, 3.42, 3.43, 3.44,3.45, 3.46, 3.47, 3.48, 3.49, 3.50, 3.51, 3.52, 3.53, 4.1, 4.2, 4.3,4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 4.10, 4.11, 4.12, 4.13, 4.14, 4.15, 4.16,4.17, 4.18, 4.19, 4.20, 4.21, 4.22, 4.23, 4.24, 4.26, 4.27, 4.28, 4.29,4.30, 4.31, 4.32, 4.33, 4.34, 4.35, 4.36, 4.37, 4.38, 4.39, 4.40, 4.41,4.42, 4.43, 4.44, 4.45, 4.46, 4.47, 4.49, 4.50, 4.51, 4.52, 4.53, 4.54,4.55, 4.56, 4.57, 4.58, 4.59, 4.60, 4.61, 4.62, 5.1, 5.2, 5.3, 5.4, 5.5,5.6, 5.7, 5.8, 5.9, 5.10, 5.11, 5.12, 5.13, 5.14, 5.15, 6.1, 6.2, 6.3,6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 6.10, 6.11, 6.12, 6.13, 6.14, 6.15, 6.16,7.1, 8, 9, 10.1, 10.2, 11.1, and 11.2 showed an EC₅₀ value of less thanabout 0.1 nM. When tested using HCV 1b-Con1 replicon assays in thepresence of 5% FBS, each title compound in Examples 1.4, 2.8, 3.3, 3.9,3.10, 3.16 and 4.25 showed an EC₅₀ value of from about 0.1 to about 1nM. When tested using HCV 1b-Con1 replicon assays in the presence of 5%FBS, each title compound in Examples 2.3, 2.7, 12.1 and 12.2 showed anEC₅₀ value of from about 1 to about 10 nM. The tile compounds of Example1.2 and 3.14 showed an EC₅₀ value of over 10 μM when tested using HCV1b-Con 1 replicon assays in the presence of 5% FBS.

When tested using HCV 2a, 2b, 3a and 4a replicon assays in the absenceof human plasma (HP), the EC₅₀ values of Example 5.1 were about at least50-fold less than those of Example 4.25 (about 200-500 pM); and the EC₅₀values of Example 3.20 were about at least 15 fold less than those ofExample 4.25. The AUC value (as defined above) of Example 5.1 was about30 fold greater than that of Example 2.9. When tested using HCV 1areplicon assays in the presence of 40% HP, the EC₅₀ value of Example 6.1against L31M, Y93H or Y93N mutant was at least 5-fold less than that ofExample 109 (about 10-100 nM) of U.S. Patent Application Publication No.2010/0317568 (U.S. patent application Ser. No. 12/813,301, hereinafterthe '301 application); and the AUC value of Example 6.1 was about 9-foldgreater than that of Example 109 of the '301 application. When testedusing HCV 2a, 2b, 3a and 4a replicon assays in the absence of HP, theEC₅₀ values of Example 4.15, as well as Example 302 of the '301application, were about 2-4 fold less than those of Example 163 (about10-50 pM) of the '301 application. When tested using HCV 2b and 4areplicon assays in the absence of HP, the EC₅₀ values of Example 251 ofthe '301 application were about 2-fold less than those of Example 163 ofthe '301 application. When tested using HCV 2a, 2b, 3a and 4a repliconassays in the absence of HP, the EC₅₀ values of Example 120 of the '301application were about at least 2-fold less than those of Example 164(about 300-1200 pM) of the '301 application, and the EC₅₀ values ofExamples 245, 256 and 271 of the '301 application were at least about10-fold less than those of Example 164 of the '301 application; the AUCvalues of Example 245, 256 and 271 were at least about 10-fold greaterthan that of Example 164.

Each compound's anti-HCV activity, can be determined by measuring theactivity of the luciferase reporter gene in the replicon in the presenceof 5% FBS. The luciferase reporter gene is placed under thetranslational control of the poliovirus IRES instead of the HCV IRES,and HuH-7 cells are used to support the replication of the replicon.

The inhibitory activities of the compounds of the present invention canbe evaluated using a variety of assays known in the art. For instance,two stable subgenomic replicon cell lines can be used for compoundcharacterization in cell culture: one derived from genotype 1a-H77 andthe other derived from genotype 1b-Con 1, obtained from University ofTexas Medical Branch, Galveston, Tex. or Apath, LLC, St. Louis, Mo.,respectively. The replicon constructs can be bicistronic subgenomicreplicons. The genotype 1a replicon construct contains NS3-NS5B codingregion derived from the H77 strain of HCV (1a-H77). The replicon alsohas a firefly luciferase reporter and a neomycin phosphotransferase(Neo) selectable marker. These two coding regions, separated by the FMDV2a protease, comprise the first cistron of the bicistronic repliconconstruct, with the second cistron containing the NS3-NS5B coding regionwith addition of adaptive mutations E1202G, K1691R, K2040R and S2204I.The 1b-Con1 replicon construct is identical to the 1a-H77 replicon,except that the HCV 5′ UTR, 3′ UTR, and NS3-NS5B coding region arederived from the 1b-Con1 strain, and the adaptive mutations are K1609E,K1846T and Y3005C. In addition, the 1b-Con1 replicon construct containsa poliovirus IRES between the HCV IRES and the luciferase gene. Repliconcell lines can be maintained in Dulbecco's modified Eagles medium (DMEM)containing 10% (v/v) fetal bovine serum (FBS), 100 IU/ml penicillin, 100mg/ml streptomycin (Invitrogen), and 200 mg/ml G418 (Invitrogen).

The inhibitory effects of the compounds of the invention on HCVreplication can be determined by measuring activity of the luciferasereporter gene. For example, replicon-containing cells can be seeded into96 well plates at a density of 5000 cells per well in 100 μl al DMEMcontaining 5% FBS. The following day compounds can be diluted indimethyl sulfoxide (DMSO) to generate a 200× stock in a series of eighthalf-log dilutions. The dilution series can then be further diluted100-fold in the medium containing 5% FBS. Medium with the inhibitor isadded to the overnight cell culture plates already containing 100 μl ofDMEM with 5% FBS. In assays measuring inhibitory activity in thepresence of human plasma, the medium from the overnight cell cultureplates can be replaced with DMEM containing 40% human plasma and 5% FBS.The cells can be incubated for three days in the tissue cultureincubators after which time 30 μA of Passive Lysis buffer (Promega) canbe added to each well, and then the plates are incubated for 15 minuteswith rocking to lyse the cells. Luciferin solution (100 μl, Promega) canbe added to each well, and luciferase activity can be measured with aVictor II luminometer (Perkin-Elmer). The percent inhibition of HCV RNAreplication can be calculated for each compound concentration and theEC₅₀ value can be calculated using nonlinear regression curve fitting tothe 4-parameter logistic equation and GraphPad Prism 4 software. Usingthe above-described assays or similar cell-based replicon assays,representative compounds of the present invention showed significantlyinhibitory activities against HCV replication.

The present invention also features pharmaceutical compositionscomprising the compounds of the invention. A pharmaceutical compositionof the present invention can comprise one or more compounds of theinvention, each of which has Formula I (or I_(A), I_(B), I_(C), I_(D),I_(E), I_(F) or I_(G)).

In addition, the present invention features pharmaceutical compositionscomprising pharmaceutically acceptable salts, solvates, or prodrugs ofthe compounds of the invention. Without limitation, pharmaceuticallyacceptable salts can be zwitterions or derived from pharmaceuticallyacceptable inorganic or organic acids or bases. Preferably, apharmaceutically acceptable salt retains the biological effectiveness ofthe free acid or base of the compound without undue toxicity,irritation, or allergic response, has a reasonable benefit/risk ratio,is effective for the intended use, and is not biologically or otherwiseundesirable.

The present invention further features pharmaceutical compositionscomprising a compound of the invention (or a salt, solvate or prodrugthereof) and another therapeutic agent. By way of illustration notlimitation, these other therapeutic agents can be selected fromantiviral agents (e.g., anti-HIV agents, anti-HBV agents, or otheranti-HCV agents such as HCV protease inhibitors, HCV polymeraseinhibitors, HCV helicase inhibitors, IRES inhibitors or NS5Ainhibitors), anti-bacterial agents, anti-fungal agents,immunomodulators, anti-cancer or chemotherapeutic agents,anti-inflammation agents, antisense RNA, siRNA, antibodies, or agentsfor treating cirrhosis or inflammation of the liver. Specific examplesof these other therapeutic agents include, but are not limited to,ribavirin, α-interferon, β-interferon, pegylated interferon-α, pegylatedinterferon-lambda, ribavirin, viramidine, R-5158, nitazoxanide,amantadine, Debio-025, NIM-811, R7128, R1626, R4048, T-1106, PSI-7977(Pharmasset) (nucleoside polymerase inhibitor), PSI-7851 (Pharmasset)(nucleoside polymerase inhibitor), PSI-938 (Pharmasset) (nucleosidepolymerase inhibitor), PF-00868554, ANA-598, IDX184 (nucleosidepolymerase inhibitor), IDX102, IDX375 (non-nucleoside polymeraseinhibitor), GS-9190 (non-nucleoside polymerase inhibitor), VCH-759,VCH-916, MK-3281, BCX-4678, MK-3281, VBY708, ANA598, GL59728, GL60667,BMS-790052 (NS5A inhibitor), BMS-791325 (protease Inhibitor),BMS-650032, BMS-824393, GS-9132, ACH-1095 (protease inhibitor), AP-H005,A-831 (Arrow Therapeutics) (NS5A inhibitor), A-689 (Arrow Therapeutics)(NS5A inhibitor), INX08189 (Inhibitex) (polymerase inhibitor), AZD2836,telaprevir (protease Inhibitor), boceprevir (protease Inhibitor),ITMN-191 (Intermune/Roche), B1-201335 (protease Inhibitor), VBY-376,VX-500 (Vertex) (protease Inhibitor), PHX-B, ACH-1625, IDX136, IDX316,VX-813 (Vertex) (protease Inhibitor), SCH 900518 (Schering-Plough),TMC-435 (Tibotec) (protease Inhibitor), ITMN-191 (Intermune, Roche)(protease Inhibitor), MK-7009 (Merck) (protease Inhibitor), IDX-PI(Novartis), BI-201335 (Boehringer Ingelheim), R7128 (Roche) (nucleosidepolymerase inhibitor), MK-3281 (Merck), MK-0608 (Merck) (nucleosidepolymerase inhibitor), PF-868554 (Pfizer) (non-nucleoside polymeraseinhibitor), PF-4878691 (Pfizer), IDX-184 (Novartis), IDX-375(Pharmasset), PPI-461 (Presidio) (NS5A inhibitor), BILB-1941 (BoehringerIngelheim), GS-9190 (Gilead), BMS-790052 (BMS), Albuferon (Novartis),ABT-333 (Abbott) (non-nucleoside polymerase inhibitor), ABT-072 (Abbott)(non-nucleoside polymerase inhibitor), ritonavir, another cytochromeP450 monooxygenase inhibitor, or any combination thereof.

In one embodiment, a pharmaceutical composition of the present inventioncomprises one or more compounds of the present invention (or salts,solvates or prodrugs thereof), and one or more other antiviral agents.

In another embodiment, a pharmaceutical composition of the presentinvention comprises one or more compounds of the present invention (orsalts, solvates or prodrugs thereof), and one or more other anti-HCVagents. For example, a pharmaceutical composition of the presentinvention can comprise a compound(s) of the present invention havingFormula I, I_(A), I_(B), I_(C), I_(D), I_(E), I_(F) or I_(G) (or a salt,solvate or prodrug thereof), and an agent selected from HCV polymeraseinhibitors (including nucleoside or non-nucleoside type of polymeraseinhibitors), HCV protease inhibitors, HCV helicase inhibitors, CD81inhibitors, cyclophilin inhibitors, IRES inhibitors, or NS5A inhibitors.

In yet another embodiment, a pharmaceutical composition of the presentinvention comprises one or more compounds of the present invention (orsalts, solvates or prodrugs thereof), and one or more other antiviralagents, such as anti-HBV, anti-HIV agents, or anti-hepatitis A,anti-hepatitis D, anti-hepatitis E or anti-hepatitis G agents.Non-limiting examples of anti-HBV agents include adefovir, lamivudine,and tenofovir. Non-limiting examples of anti-HIV drugs includeritonavir, lopinavir, indinavir, nelfinavir, saquinavir, amprenavir,atazanavir, tipranavir, TMC-114, fosamprenavir, zidovudine, lamivudine,didanosine, stavudine, tenofovir, zalcitabine, abacavir, efavirenz,nevirapine, delavirdine, TMC-125, L-870812, S-1360, enfuvirtide, T-1249,or other HIV protease, reverse transcriptase, integrase or fusioninhibitors. Any other desirable antiviral agents can also be included ina pharmaceutical composition of the present invention, as appreciated bythose skilled in the art.

In a preferred embodiment, a pharmaceutical composition of the inventioncomprises a compound of the invention (e.g., a compound of Formula I,I_(A), I_(B), I_(C), I_(D), I_(E), I_(F) or I_(G), or preferably acompound described hereinabove, or a salt, solvate or prodrug thereof),and a HCV protease inhibitor. In another preferred embodiment, apharmaceutical composition of the invention comprises a compound of theinvention (e.g., a compound of Formula I, I_(A), I_(B), I_(C), I_(D),I_(E), I_(F) or I_(G), or preferably a compound described hereinabove,or a salt, solvate or prodrug thereof), and a HCV polymerase inhibitor(e.g., a non-nucleoside polymerase inhibitor, or preferably a nucleosidepolymerase inhibitor). In yet another preferred embodiment, apharmaceutical composition of the present invention comprises (1) acompound of the invention (e.g., a compound of Formula I, I_(A), I_(B),I_(C), I_(D), I_(E), I_(F) or I_(G), or preferably a compound describedhereinabove, or a salt, solvate or prodrug thereof), (2) a HCV proteaseinhibitor, and (3) a HCV polymerase inhibitor (e.g., a non-nucleosidepolymerase inhibitor, or preferably a nucleoside polymerase inhibitor).Non-limiting examples of protease and polymerase inhibitors aredescribed above.

In still another embodiment, a pharmaceutical composition of theinvention comprises (1) a compound of Formula I, I_(A), I_(B), I_(C),I_(D), I_(E), I_(F) or I_(G), or preferably a compound selected from thetitle compounds of the above Examples or Table 5, or a salt, solvate orprodrug thereof, and (2) one or more HCV inhibitors/modulators selectedfrom ABT-072 (Abbott), ABT-333 (Abbott), ACH-1095 (Achillion), ACH-1625(Achillion), ACH-2684 (Achillion), ACH-2928 (Achillion), alisporovir,ANA-598 (Anadys), ANA-773 (Anadys), AVL-181 (Avila), AVL-192 (Avila),AZD2836 (Astra-Zeneca), AZD7295 (Astra-Zeneca), BCX-4678 (BioCryst),BI-201335 (Boehringer Ingelheim), BI-207127 (Boehringer Ingelheim),BILB-1941 (Boehringer Ingelheim), BMS-650032 (BMS), BMS-790052 (BMS),BMS-791325 (BMS), BMS-824393 (BMS), boceprevir, CTS-1027 (Conatus),danoprevir, EDP-239 (Enanta), filibuvir, GL59728 (Glaxo), GL60667(Glaxo), GS-5885 (Gilead), GS-6620 (Gilead), GS-9132 (Gilead), GS-9256(Gilead), GS-9451 (Gilead), GS-9620 (Gilead), GS-9669 (Gilead),GSK625433 (GlaxoSmithKline), IDX-102 (Idenix), IDX-136 (Idenix), IDX-184(Idenix), IDX-316 (Idenix), IDX-320 (Idenix), IDX-375 (Idenix), INX-189(Inhibitex), ITX-4520 (iTherx), ITX-5061 (iTherx), MK-0608 (Merck),MK-3281 (Merck), MK-5172 (Merck), narlaprevir, NM-811 (Novartis),PF-4878691 (Pfizer), PHX-1766 (Phenomix), PPI-1301 (Presidio), PPI-461(Presidio), PSI-7977 (Pharmasset), PSI-938 (Pharmasset), RG7128 (Roche),RO5303253 (Roche), SCY-635 (Scynexis), tegobuvir, telaprevir, TMC-435(Tibotec), TMC-647055 (Tibotec), TMC64912 (Medivir), vaniprevir, VBY708(Virobay), VCH-759 (Vertex & ViraChem), VCH-916 (ViraChem), VX-222(VCH-222) (Vertex & ViraChem), VX-500 (Vertex), VX-759 (Vertex), VX-813(Vertex), VX-985 (Vertex), or a combination thereof.

In another embodiment, a pharmaceutical composition of the inventioncomprises (1) a compound of Formula I, I_(A), I_(B), I_(C), I_(D),I_(F), I_(F) or I_(D), or preferably a compound selected from the titlecompounds of the above Examples or Table 5, or a salt, solvate orprodrug thereof, and (2) one or more HCV protease inhibitors selectedfrom ACH-1095 (Achillion), ACH-1625 (Achillion), ACH-2684 (Achillion),AVL-181 (Avila), AVL-192 (Avila), BI-201335 (Boehringer Ingelheim),BMS-650032 (BMS), boceprevir, danoprevir, GS-9132 (Gilead), GS-9256(Gilead), GS-9451 (Gilead), IDX-136 (Idenix), IDX-316 (Idenix), IDX-320(Idenix), MK-5172 (Merck), narlaprevir, PHX-1766 (Phenomix), telaprevir,TMC-435 (Tibotec), vaniprevir, VBY708 (Virobay), VX-500 (Vertex), VX-813(Vertex), VX-985 (Vertex), or a combination thereof.

In yet another preferred embodiment, a pharmaceutical composition of theinvention comprises (1) a compound of Formula I, I_(A), I_(B), I_(C),I_(D), I_(E), I_(F) or I_(G), or preferably a compound selected from thetitle compounds of the above Examples or Table 5, or a salt, solvate orprodrug thereof, and (2) one or more HCV polymerase inhibitors selectedfrom ABT-072 (Abbott), ABT-333 (Abbott), ANA-598 (Anadys), BI-207127(Boehringer Ingelheim), BILB-1941 (Boehringer Ingelheim), BMS-791325(BMS), filibuvir, GL59728 (Glaxo), GL60667 (Glaxo), GS-9669 (Gilead),IDX-375 (Idenix), MK-3281 (Merck), tegobuvir, TMC-647055 (Tibotec),VCH-759 (Vertex & ViraChem), VCH-916 (ViraChem), VX-222 (VCH-222)(Vertex & ViraChem), VX-759 (Vertex), GS-6620 (Gilead), IDX-102(Idenix), IDX-184 (Idenix), INX-189 (Inhibitex), MK-0608 (Merck),PSI-7977 (Pharmasset), PSI-938 (Pharmasset), RG7128 (Roche), TMC64912(Medivir), GSK625433 (GlaxoSmithKline), BCX-4678 (BioCryst), or acombination thereof. The polymerase inhibitor(s) can include (i) one ormore nucleotide polymerase inhibitors selected from GS-6620 (Gilead),IDX-102 (Idenix), IDX-184 (Idenix), INX-189 (Inhibitex), MK-0608(Merck), PSI-7977 (Pharmasset), PSI-938 (Pharmasset), RG7128 (Roche),TMC64912 (Medivir), or a combination therefore; or (ii) one or morenon-nucleoside polymerase inhibitors selected from ABT-072 (Abbott),ABT-333 (Abbott), ANA-598 (Anadys), BI-207127 (Boehringer Ingelheim),BILB-1941 (Boehringer Ingelheim), BMS-791325 (BMS), filibuvir, GL59728(Glaxo), GL60667 (Glaxo), GS-9669 (Gilead), IDX-375 (Idenix), MK-3281(Merck), tegobuvir, TMC-647055 (Tibotec), VCH-759 (Vertex & ViraChem),VCH-916 (ViraChem), VX-222 (VCH-222) (Vertex & ViraChem), VX-759(Vertex), or a combination thereof; or (iii) both a nucleotidepolymerase inhibitor(s) and a non-nucleoside polymerase inhibitor(s).

In a further embodiment, a pharmaceutical composition of the inventioncomprises (1) a compound of Formula I, I_(A), I_(D), I_(C), I_(D),I_(E), I_(F) or I_(G), or preferably a compound selected from the titlecompounds of the above Examples or Table 5, or a salt, solvate orprodrug thereof, (2) one or more HCV protease inhibitors selected fromACH-1095 (Achillion), ACH-1625 (Achillion), ACH-2684 Achillion), AVL-181(Avila), AVL-192 (Avila), BI-201335 (Boehringer Ingelheim), BMS-650032(BMS), boceprevir, danoprevir, GS-9132 (Gilead), GS-9256 (Gilead),GS-9451 (Gilead), IDX-136 (Idenix), IDX-316 (Idenix), IDX-320 (Idenix),MK-5172 (Merck), narlaprevir, PHX-1766 (Phenomix), telaprevir, TMC-435(Tibotec), vaniprevir, VBY708 (Virobay), VX-500 (Vertex), VX-813(Vertex), VX-985 (Vertex), or a combination thereof, and (3) one or moreHCV polymerase inhibitors selected from ABT-072 (Abbott), ABT-333(Abbott), ANA-598 (Anadys), BI-207127 (Boehringer Ingelheim), BILB-1941(Boehringer Ingelheim), BMS-791325 (BMS), filibuvir, GL59728 (Glaxo),GL60667 (Glaxo), GS-9669 (Gilead), IDX-375 (Idenix), MK-3281 (Merck),tegobuvir, TMC-647055 (Tibotec), VCH-759 (Vertex & ViraChem), VCH-916(ViraChem), VX-222 (VCH-222) (Vertex & ViraChem), VX-759 (Vertex),GS-6620 (Gilead), IDX-102 (Idenix), IDX-184 (Idenix), INX-189(Inhibitex), MK-0608 (Merck), PSI-7977 (Pharmasset), PSI-938(Pharmasset), RG7128 (Roche), TMC64912 (Medivir), GSK625433(GlaxoSmithKline), BCX-4678 (BioCryst), ore a combination thereof. Thepolymerase inhibitor(s) can include (i) one or more nucleotidepolymerase inhibitors selected from GS-6620 (Gilead), IDX-102 (Idenix),IDX-184 (Idenix), INX-189 (Inhibitex), MK-0608 (Merck), PSI-7977(Pharmasset), PSI-938 (Pharmasset), RG7128 (Roche), TMC64912 (Medivir),or a combination therefore; or (ii) one or more non-nucleosidepolymerase inhibitors selected from ABT-072 (Abbott), ABT-333 (Abbott),ANA-598 (Anadys), BI-207127 (Boehringer Ingelheim), BILB-1941(Boehringer Ingelheim), BMS-791325 (BMS), filibuvir, GL59728 (Glaxo),GL60667 (Glaxo), GS-9669 (Gilead), IDX-375 (Idenix), MK-3281 (Merck),tegobuvir, TMC-647055 (Tibotec), VCH-759 (Vertex & ViraChem), VCH-916(ViraChem), VX-222 (VCH-222) (Vertex & ViraChem), VX-759 (Vertex), or acombination thereof; or (iii) both a nucleotide polymerase inhibitor(s)and a non-nucleoside polymerase inhibitor(s).

In still another embodiment, a pharmaceutical composition of theinvention comprises (1) a compound of Formula I, I_(A), I_(B), I_(C),I_(D), I_(E), I_(F) or I_(G), or preferably a compound selected from thetitle compounds of the above Examples or Table 5, or a salt, solvate orprodrug thereof, and (2) an cyclophilin inhibitor (e.g., alisporovir,NM-811 (Novartis), SCY-635 (Scynexis)), an entry inhibitor (e.g.,ITX-4520 (iTherx) or ITX-5061 (iTherx)), another NS5A inhibitor (e.g.),or a TLR-7 agonist (e.g., GS-9620 (Gilead) or PF-4878691 (Pfizer)), and(3) optionally one or more HCV protease or polymerase inhibitorsdescribed above.

A pharmaceutical composition containing multiple active ingredients canbe either a co-formulated product, a co-packaged product, or acombination thereof.

A pharmaceutical composition of the present invention typically includesa pharmaceutically acceptable carrier or excipient. Non-limitingexamples of suitable pharmaceutically acceptable carriers/excipientsinclude sugars (e.g., lactose, glucose or sucrose), starches (e.g., cornstarch or potato starch), cellulose or its derivatives (e.g., sodiumcarboxymethyl cellulose, ethyl cellulose or cellulose acetate), oils(e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil,corn oil or soybean oil), glycols (e.g., propylene glycol), bufferingagents (e.g., magnesium hydroxide or aluminum hydroxide), agar, alginicacid, powdered tragacanth, malt, gelatin, talc, cocoa butter,pyrogen-free water, isotonic saline, Ringer's solution, ethanol, orphosphate buffer solutions. Lubricants, coloring agents, releasingagents, coating agents, sweetening, flavoring or perfuming agents,preservatives, or antioxidants can also be included in a pharmaceuticalcomposition of the present invention.

The pharmaceutical compositions of the present invention can beformulated based on their routes of administration using methods wellknown in the art. For example, a sterile injectable preparation can beprepared as a sterile injectable aqueous or oleagenous suspension usingsuitable dispersing or wetting agents and suspending agents.Suppositories for rectal administration can be prepared by mixing drugswith a suitable nonirritating excipient such as cocoa butter orpolyethylene glycols which are solid at ordinary temperatures but liquidat the rectal temperature and will therefore melt in the rectum andrelease the drugs. Solid dosage forms for oral administration can becapsules, tablets, pills, powders or granules. In such solid dosageforms, the active compounds can be admixed with at least one inertdiluent such as sucrose lactose or starch. Solid dosage forms may alsocomprise other substances in addition to inert diluents, such aslubricating agents. In the case of capsules, tablets and pills, thedosage forms may also comprise buffering agents. Tablets and pills canadditionally be prepared with enteric coatings. Liquid dosage forms fororal administration can include pharmaceutically acceptable emulsions,solutions, suspensions, syrups or elixirs containing inert diluentscommonly used in the art. Liquid dosage forms may also comprise wetting,emulsifying, suspending, sweetening, flavoring, or perfuming agents. Thepharmaceutical compositions of the present invention can also beadministered in the form of liposomes, as described in U.S. Pat. No.6,703,403. Formulation of drugs that are applicable to the presentinvention is generally discussed in, for example, Hoover, John E.,REMINGTON′S PHARMACEUTICAL SCIENCES (Mack Publishing Co., Easton, Pa.:1975), and Lachman, L., eds., PHARMACEUTICAL DOSAGE FORMS (MarcelDecker, New York, N.Y., 1980).

Any compound described herein, or a pharmaceutically acceptable saltthereof, can be used to prepared pharmaceutical compositions of thepresent invention.

In a preferred embodiment, a compound of the invention (e.g., a compoundof Formula I, I_(A), I_(B), I_(C), I_(D), I_(E), I_(F) or I_(G), orpreferably a compound described hereinabove, or a salt, solvate orprodrug thereof) is formulated in a solid dispersion, where the compoundof the invention can be molecularly dispersed in an amorphous matrixwhich comprises a pharmaceutically acceptable, hydrophilic polymer. Thematrix may also contain a pharmaceutically acceptable surfactant.Suitable solid dispersion technology for formulating a compound of theinvention includes, but is not limited to, melt-extrusion, spray-drying,co-precipitation, freeze drying, or other solvent evaporationtechniques, with melt-extrusion and spray-drying being preferred. In oneexample, a compound of the invention is formulated in a solid dispersioncomprising copovidone and vitamin E TPGS. In another example, a compoundof the invention is formulated in a solid dispersion comprisingcopovidone and Span 20.

A solid dispersion described herein may contain at least 30% by weightof a pharmaceutically acceptable hydrophilic polymer or a combination ofsuch hydrophilic polymers. Preferably, the solid dispersion contains atleast 40% by weight of a pharmaceutically acceptable hydrophilic polymeror a combination of such hydrophilic polymers. More preferably, thesolid dispersion contains at least 50% (including, e.g., at least 60%,70%, 80% or 90%) by weight of a pharmaceutically acceptable hydrophilicpolymer or a combination of such polymers. A solid dispersion describedherein may also contain at least 1% by weight of a pharmaceuticallyacceptable surfactant or a combination of such surfactants. Preferably,the solid dispersion contains at least 2% by weight of apharmaceutically acceptable surfactant or a combination of suchsurfactants. More preferably, the solid dispersion contains from 4% to20% by weight of the surfactant(s), such as from 5% to 10% by weight ofthe surfactant(s). In addition, a solid dispersion described herein maycontain at least 1% by weight of a compound of the invention, preferablyat least 5%, including, e.g., at least 10%. In one example, the soliddispersion comprises 5% of a compound of the invention (e.g., a compoundof Formula I, I_(A), I_(B), I_(C), I_(D), I_(E), I_(F) or I_(G), orpreferably a compound described hereinabove, or a salt, solvate orprodrug thereof), which is molecularly dispersed in a an amorphousmatrix comprising 7% Vitamin E-TPGS and 88% copovidone; the soliddispersion can also be mixed with other excipients such asmannitol/aerosil (99:1), and the weight ratio of the solid dispersionover the other excipients can range from 5:1 to 1:5 with 1:1 beingpreferred. In another example, the solid dispersion comprises 5% of acompound of the invention (e.g., a compound of Formula I, I_(A), I_(B),I_(C), I_(D), I_(F), I_(F) or I_(G), or preferably a compound describedhereinabove, or a salt, solvate or prodrug thereof), which ismolecularly dispersed in a an amorphous matrix comprising 5% Span 20 and90% copovidone; the solid dispersion can also be mixed with otherexcipients such as mannitol/aerosil (99:1), the solid dispersion canalso be mixed with other excipients such as mannitol/aerosil (99:1), andthe weight ratio of the solid dispersion over the other excipients canrange from 5:1 to 1:5 with 1:1 being preferred.

Various additives can also be included in or mixed with the soliddispersion. For instance, at least one additive selected from flowregulators, binders, lubricants, fillers, disintegrants, plasticizers,colorants, or stabilizers may be used in compressing the soliddispersion to tablets. These additives can be mixed with ground ormilled solid dispersion before compacting. Disintegrants promote a rapiddisintegration of the compact in the stomach and keeps the liberatedgranules separate from one another. Non-limiting examples of suitabledisintegrants are cross-linked polymers such as cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethylcellulose or sodiumcroscarmellose. Non-limiting examples of suitable fillers (also referredto as bulking agents) are lactose monohydrate, calciumhydrogenphosphate, microcrystalline cellulose (e.g., Avicell),silicates, in particular silicium dioxide, magnesium oxide, talc, potatoor corn starch, isomalt, or polyvinyl alcohol. Non-limiting examples ofsuitable flow regulators include highly dispersed silica (e.g.,colloidal silica such as Aerosil), and animal or vegetable fats orwaxes. Non-limiting examples of suitable lubricants include polyethyleneglycol (e.g., having a molecular weight of from 1000 to 6000), magnesiumand calcium stearates, sodium stearyl fumarate, and the like.Non-limiting examples of stabilizers include antioxidants, lightstabilizers, radical scavengers, or stabilizers against microbialattack.

The present invention further features methods of using the compounds ofthe present invention (or salts, solvates or prodrugs thereof) toinhibit HCV replication. The methods comprise contacting cells infectedwith HCV virus with an effective amount of a compound of the presentinvention (or a salt, solvate or prodrug thereof), thereby inhibitingthe replication of HCV virus in the cells. As used herein, “inhibiting”means significantly reducing, or abolishing, the activity beinginhibited (e.g., viral replication). In many cases, representativecompounds of the present invention can reduce the replication of HCVvirus (e.g., in an HCV replicon assay as described above) by at least10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more.

The compounds of the present invention may inhibit one or more HCVsubtypes. Examples of HCV subtypes that are amenable to the presentinvention include, but are not be limited to, HCV genotypes 1, 2, 3, 4,5 and 6, including HCV genotypes 1a, 1b, 2a, 2b, 2c, 3a or 4a. In oneembodiment, a compound or compounds of the present invention (or salts,solvates or prodrugs thereof) are used to inhibit the replication of HCVgenotype 1a. In another embodiment, a compound or compounds of thepresent invention (or salts, solvates or prodrugs thereof) are used toinhibit the replication of HCV genotype 1b. In still another embodiment,a compound or compounds of the present invention (or salts, solvates orprodrugs thereof) are used to inhibit the replication of both HCVgenotypes 1a and 1b.

The present invention also features methods of using the compounds ofthe present invention (or salts, solvates or prodrugs thereof) to treatHCV infection. The methods typically comprise administering atherapeutic effective amount of a compound of the present invention (ora salt, solvate or prodrug thereof), or a pharmaceutical compositioncomprising the same, to an HCV patient, thereby reducing the HCV virallevel in the blood or liver of the patient. As used herein, the term“treating” refers to reversing, alleviating, inhibiting the progress of,or preventing the disorder or condition, or one or more symptoms of suchdisorder or condition to which such term applies. The term “treatment”refers to the act of treating. In one embodiment, the methods compriseadministering a therapeutic effective amount of two or more compounds ofthe present invention (or salts, solvates or prodrugs thereof), or apharmaceutical composition comprising the same, to an HCV patient,thereby reducing the HCV viral level in the blood or liver of thepatient.

A compound of the present invention (or a salt, solvate or prodrugthereof) can be administered as the sole active pharmaceutical agent, orin combination with another desired drug, such as other anti-HCV agents,anti-HIV agents, anti-HBV agents, anti-hepatitis A agents,anti-hepatitis D agents, anti-hepatitis E agents, anti-hepatitis Gagents, or other antiviral drugs. Any compound described herein, or apharmaceutically acceptable salt thereof, can be employed in the methodsof the present invention. In one embodiment, the present inventionfeatures methods of treating HCV infection, wherein said methodscomprise administering a compound of the invention (e.g., a compound ofFormula I, I_(A), I_(B), I_(C), I_(D), I_(E), I_(F) or I_(G), orpreferably a compound described hereinabove, or a salt, solvate orprodrug thereof), interferon and ribavirin to an HCV patient. Theinterferon preferably is α-interferon, and more preferably, pegylatedinterferon-α such as PEGASYS (peginterferon alfa-2a).

In another embodiment, the present invention features methods oftreating HCV infection, wherein said methods comprise administering acompound of the invention (e.g., a compound of Formula I, I_(A), I_(B),I_(C), I_(D), I_(E), I_(F) or I_(G), or preferably a compound selectedfrom the title compounds of the above Examples or Table 5, or a salt,solvate or prodrug thereof), and one or more HCV inhibitors/modulatorsdescribed above, with or without interferon.

A compound of the present invention (or a salt, solvent or prodrugthereof) can be administered to a patient in a single dose or divideddoses. A typical daily dosage can range, without limitation, from 0.1 to200 mg/kg body weight, such as from 0.25 to 100 mg/kg body weight.Single dose compositions can contain these amounts or submultiplesthereof to make up the daily dose. Preferably, each dosage contains asufficient amount of a compound of the present invention that iseffective in reducing the HCV viral load in the blood or liver of thepatient. The amount of the active ingredient, or the active ingredientsthat are combined, to produce a single dosage form may vary dependingupon the host treated and the particular mode of administration. It willbe understood that the specific dose level for any particular patientwill depend upon a variety of factors including the activity of thespecific compound employed, the age, body weight, general health, sex,diet, time of administration, route of administration, rate ofexcretion, drug combination, and the severity of the particular diseaseundergoing therapy.

The present invention further features methods of using thepharmaceutical compositions of the present invention to treat HCVinfection. The methods typically comprise administering a pharmaceuticalcomposition of the present invention to an HCV patient, thereby reducingthe HCV viral level in the blood or liver of the patient. Anypharmaceutical composition described herein can be used in the methodsof the present invention.

In addition, the present invention features use of the compounds orsalts of the present invention for the manufacture of medicaments forthe treatment of HCV infection. Any compound described herein, or apharmaceutically acceptable salt thereof, can be used to makemedicaments of the present invention.

The compounds of the present invention can also be isotopicallysubstituted. Preferred isotopic substitution include substitutions withstable or nonradioactive isotopes such as deuterium, ¹³C, ¹⁵N or ¹⁸O.Incorporation of a heavy atom, such as substitution of deuterium forhydrogen, can give rise to an isotope effect that could alter thepharmacokinetics of the drug. In one example, at least 5 mol % (e.g., atleast 10 mol %) of hydrogen in a compound of the present invention issubstituted with deuterium. In another example, at least 25 mole % ofhydrogen in a compound of the present invention is substituted withdeuterium. In a further example, at least 50, 60, 70, 80 or 90 mole % ofhydrogen in a compound of the present invention is substituted withdeuterium. The natural abundance of deuterium is about 0.015%. Deuteriumsubstitution or enrichment can be achieved, without limitation, byeither exchanging protons with deuterium or by synthesizing the moleculewith enriched or substituted starting materials. Other methods known inthe art can also be used for isotopic substitutions.

The foregoing description of the present invention provides illustrationand description, but is not intended to be exhaustive or to limit theinvention to the precise one disclosed. Modifications and variations arepossible in light of the above teachings or may be acquired frompractice of the invention. Thus, it is noted that the scope of theinvention is defined by the claims and their equivalents.

1. A compounds having Formula I, or a pharmaceutically acceptable saltthereof,

wherein: X is C₃-C₁₂carbocycle or 3- to 12-membered heterocycle, and isoptionally substituted with one or more R_(A) or R_(F); L₁ and L₂ areeach independently selected from bond; or C₁-C₆alkylene, C₂-C₆alkenyleneor C₂-C₆alkynylene, each of which is independently optionallysubstituted at each occurrence with one or more R_(L); L₃ is bond or-L_(S)-K-L_(S)′-, wherein K is selected from bond, —O—, —S—, —N(R_(B))—,—C(O)—, —S(O)₂—, —S(O)—, —OS(O)—, —OS(O)₂—, —S(O)₂O—, —S(O)O—, —C(O)O—,—OC(O)—, —OC(O)O—, —C(O)N(R_(B))—, —N(R_(B))C(O)—, —N(R_(B))C(O)O—,—OC(O)N(R_(B))—, —N(R_(B))S(O)—, —N(R_(B))S(O)₂—, —S(O)N(R_(B))—,—S(O)₂N(R_(B))—, —C(O)N(R_(B))C(O)—, —N(R_(B))C(O)N(R_(B)′)-,—N(R_(B))SO₂N(R_(B)′)-, or —N(R_(B))S(O)N(R_(B)′)—; A and B are eachindependently C₃-C₁₂carbocycle or 3- to 12-membered heterocycle, and areeach independently optionally substituted with one or more R_(A); D isC₃-C₁₂carbocycle or 3- to 12-membered heterocycle, and is optionallysubstituted with one or more R_(A); or D is C₃-C₁₂carbocycle or 3- to12-membered heterocycle which is substituted with J and optionallysubstituted with one or more R_(A), where J is C₃-C₁₂carbocycle or 3- to12-membered heterocycle and is optionally substituted with one or moreR_(A), or J is —SF₅; or D is hydrogen or R_(A); Y is selected from-T′—C(R₁R₂)N(R₅)-T—R_(D), -T′—C(R₃R₄)C(R₆R₇)-T—R_(D), -L_(K)-T—R_(n), or-L_(K)-E; R₁ and R₂ are each independently R_(C), and R₅ is R_(B); or R₁is R_(C), and R₂ and R₅, taken together with the atoms to which they areattached, form a 3- to 12-membered heterocycle which is optionallysubstituted with one or more R_(A); R₃, R₄, R₆, and R₇ are eachindependently R_(C); or R₃ and R₆ are each independently R_(C), and R₄and R₇, taken together with the atoms to which they are attached, form a3- to 12-membered carbocycle or heterocycle which is optionallysubstituted with one or more R_(A); Z is selected from-T′—C(R₈R₉)N(R₁₂)-T—R_(D), -T′—C(R₁₀R₁₁)C(R₁₃R₁₄)-T—R_(D),-L_(K)-T—R_(D) or -L_(K)-E; R₈ and R₉ are each independently R_(C), andR₁₂ is R_(B); or R₈ is R_(C), and R₉ and R₁₂, taken together with theatoms to which they are attached, form a 3- to 12-membered heterocyclewhich is optionally substituted with one or more R_(A); R₁₀, R₁₁, R₁₃,and R₁₄ are each independently R_(C); or R₁₀ and R₁₃ are eachindependently R_(C), and R₁₁ and R₁₄, taken together with the atoms towhich they are attached, form a 3- to 12-membered carbocycle orheterocycle which is optionally substituted with one or more R_(A); Tand T′ are each independently selected at each occurrence from bond,-L_(S)-, -L_(S)-M-L_(S)′-, or -L_(S)-M-L_(S)′-M′-L_(S)″—, wherein M andM′ are each independently selected at each occurrence from bond, —O—,—S—, —N(R_(B))—, —C(O)—, —S(O)₂—, —S(O)—, —OS(O)—, —OS(O)₂—, —S(O)₂O—,—S(O)O—, —C(O)O—, —OC(O)—, —OC(O)O—, —C(O)N(R_(B))—, —N(R_(B))C(O)—,—N(R_(B))C(O)O—, —OC(O)N(R_(B))—, —N(R_(B))S(O)—, —N(R_(B))S(O)₂—,—S(O)N(R_(B))—, —S(O)₂N(R_(B))—, —C(O)N(R_(B))C(O)—,—N(R_(B))C(O)N(R_(B))—, —N(R_(B))SO₂N(R_(B)′)-, —N(R_(B))S(O)N(R_(B)′)-,C₃-C₁₂carbocycle or 3- to 12-membered heterocycle, and wherein saidC₃-C₁₂carbocycle and 3- to 12-membered heterocycle are eachindependently optionally substituted at each occurrence with one or moreR_(A); L_(K) is independently selected at each occurrence from bond,-L_(S)-N(R_(B))C(O)-L_(S)′- or -L_(S)-C(O)N(R_(B))-L_(S)′-; orC₁-C₆alkylene, C₂-C₆alkenylene or C₂-C₆alkynylene, each of which isindependently optionally substituted at each occurrence with one or moreR_(L); or C₃-C₁₂carbocycle or 3- to 12-membered heterocycle, each ofwhich is independently optionally substituted at each occurrence withone or more R_(A); E is independently selected at each occurrence fromC₃-C₁₂carbocycle or 3- to 12-membered heterocycle, and is independentlyoptionally substituted at each occurrence with one or more R_(A); R_(D)is each independently selected at each occurrence from hydrogen orR_(A); R_(A) is independently selected at each occurrence from halogen,nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, or -L_(S)-R_(E),wherein two adjacent R_(A), taken together with the atoms to which theyare attached and any atoms between the atoms to which they are attached,can optionally form carbocycle or heterocycle; R_(B) and R_(B)′ are eachindependently selected at each occurrence from hydrogen; or C₁-C₆alkyl,C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is independently optionallysubstituted at each occurrence with one or more substituents selectedfrom halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,phosphonoxy, phosphono, thioxo, formyl, cyano or 3- to 6-memberedcarbocycle or heterocycle; or 3- to 6-membered carbocycle orheterocycle; wherein each 3- to 6-membered carbocycle or heterocycle inR_(B) or R_(B)′ is independently optionally substituted at eachoccurrence with one or more substituents selected from halogen, hydroxy,mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo,formyl, cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl,C₂-C₆haloalkenyl or C₂-C₆haloalkynyl; R_(C) is independently selected ateach occurrence from hydrogen, halogen, hydroxy, mercapto, amino,carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; orC₁-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is independentlyoptionally substituted at each occurrence with one or more substituentsselected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,phosphonoxy, phosphono, thioxo, formyl, cyano or 3- to 6-memberedcarbocycle or heterocycle; or 3- to 6-membered carbocycle orheterocycle; wherein each 3- to 6-membered carbocycle or heterocycle inR_(C) is independently optionally substituted at each occurrence withone or more substituents selected from halogen, hydroxy, mercapto,amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl,cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl,C₂-C₆haloalkenyl or C₂-C₆haloalkynyl; R_(E) is independently selected ateach occurrence from —O—R_(S), —S—R_(S), —C(O)R_(S), —OC(O)R_(S),—C(O)OR_(S), —N(R_(S)R_(S)′), —S(O)R_(S), —SO₂R_(S),—C(O)N(R_(S)R_(S)′), —N(R_(S))C(O)R_(S)′, —N(R_(S))C(O)N(R_(S)′R_(S)″),—N(R_(S))SO₂R_(S)′, —SO₂N(R_(S)R_(S)′), —N(R_(S))SO₂N(R_(S)′R_(S)″),—N(R_(S))S(O)N(R_(S)′R_(S)″), —OS(O)—R_(S), —OS(O)₂—R_(S), —S(O)₂OR_(S),—S(O)OR_(S), —OC(O)OR_(S), —N(R_(S))C(O)OR_(S)′, —OC(O)N(R_(S)R_(S)′),—N(R_(S))S(O)—R_(S)′, —S(O)N(R_(S)R_(S)′), —P(O)(OR_(S))₂, or—C(O)N(R_(S))C(O)—R_(S)′; or C₁-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl,each of which is independently optionally substituted at each occurrencewith one or more substituents selected from halogen, hydroxy, mercapto,amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl orcyano; or C₃-C₆carbocycle or 3- to 6-membered heterocycle, each of whichis independently optionally substituted at each occurrence with one ormore substituents selected from halogen, hydroxy, mercapto, amino,carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano,C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl,C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, C(O)OR_(S), or —N(R_(S)R_(S)′);R_(F) is independently selected at each occurrence from C₁-C₁₀alkyl,C₂-C₁₀alkenyl or C₂-C₁₀alkynyl, each of which contains 0, 1, 2, 3, 4 or5 heteroatoms selected from O, S or N and is optionally substituted withone or more R_(L); or —(R_(X)—R_(Y))_(Q)—(R_(X)—R_(Y)′), wherein Q is 0,1, 2, 3 or 4, and each R_(X) is independently O, S or N(R_(B)), whereineach R_(Y) is independently C₁-C₆alkylene, C₂-C₆alkenylene orC₂-C₆alkynylene each of which is independently optionally substitutedwith one or more substituents selected from halogen, hydroxy, mercapto,amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl orcyano, and wherein each R_(Y)′ is independently C₁-C₆alkyl, C₂-C₆alkenylor C₂-C₆alkynyl each of which is independently optionally substitutedwith one or more substituents selected from halogen, hydroxy, mercapto,amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl orcyano; R_(L) is independently selected at each occurrence from halogen,nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, —O—R_(S), —S—R_(S),—C(O)R_(S), —OC(O)R_(S), —C(O)OR_(S), —N(R_(S)R_(S)′), —S(O)R_(S),—SO₂R_(S), —C(O)N(R_(S)R_(S)′) or —N(R_(S))C(O)R_(S)′; orC₃-C₆carbocycle or 3- to 6-membered heterocycle, each of which isindependently optionally substituted at each occurrence with one or moresubstituents selected from halogen, hydroxy, mercapto, amino, carboxy,nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl, C₂-C₆haloalkenyl orC₂-C₆haloalkynyl; wherein two adjacent R_(L), taken together with theatoms to which they are attached and any atoms between the atoms towhich they are attached, can optionally form carbocycle or heterocycle;L_(S), L_(S)′ and L_(S)″ are each independently selected at eachoccurrence from bond; or C₁-C₆alkylene, C₂-C₆alkenylene orC₂-C₆alkynylene, each of which is independently optionally substitutedat each occurrence with one or more R_(L); and R_(S), R_(S)′ and R_(S)″are each independently selected at each occurrence from hydrogen;C₁-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is independentlyoptionally substituted at each occurrence with one or more substituentsselected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,phosphonoxy, phosphono, thioxo, formyl, cyano, —O—C₁-C₆alkyl,—O—C₁-C₆alkylene—O—C₁-C₆alkyl, or 3- to 6-membered carbocycle orheterocycle; or 3- to 6-membered carbocycle or heterocycle; wherein each3- to 6-membered carbocycle or heterocycle in R_(S), R_(S)′ or R_(S)′ isindependently optionally substituted at each occurrence with one or moresubstituents selected from halogen, hydroxy, mercapto, amino, carboxy,nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl, C₂-C₆haloalkenyl orC₂-C₆haloalkynyl.
 2. A compounds having Formula I_(B), or apharmaceutically acceptable salt thereof,

wherein: R_(C)′ is each independently selected from R_(C); R_(D)′ iseach independently selected from R_(D); R₂ and R₅, taken together withthe atoms to which they are attached, form a 3- to 12-memberedheterocycle which is optionally substituted with one or more R_(A); R₉and R₁₂, taken together with the atoms to which they are attached, forma 3- to 12-membered heterocycle which is optionally substituted with oneor more R_(A); X is

wherein X₃ is N and is directly linked to -L₃-D, and X is optionallysubstituted with one or more R_(A) or R_(F); L₁, L₂, and L₃ are bond; Ais

and is optionally substituted with one or more R_(A); B is

and is optionally substituted with one or more R_(A); D is phenyl, andis substituted with J and optionally substituted with one or more R_(A);J is C₃-C₆carbocycle, 3- to 6-membered heterocycle, 6- to 12-memberedbicycle, 10- to 15-membered tricycle, or 13- to 15-membered carbocycleor heterocycle, and J is optionally substituted with one or more R_(A);-T-R_(D)′ is each independently selected from—C(O)-L_(Y)′—N(R_(B))C(O)—R_(D)′ or —C(O)-L_(Y)′—N(R_(B))C(O)O—R_(D)′,wherein L_(Y)′ is C₁-C₆alkylene and optionally substituted with one ormore substituents selected from R_(L); R_(D) is each independentlyselected at each occurrence from hydrogen or R_(A); R_(A) isindependently selected at each occurrence from halogen, nitro, oxo,phosphonoxy, phosphono, thioxo, cyano, or -L_(S)-R_(E), wherein twoadjacent R_(A), taken together with the atoms to which they are attachedand any atoms between the atoms to which they are attached, canoptionally form carbocycle or heterocycle; R_(B) and R_(B)′ are eachindependently selected at each occurrence from hydrogen; or C₁-C₆alkyl,C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is independently optionallysubstituted at each occurrence with one or more substituents selectedfrom halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,phosphonoxy, phosphono, thioxo, formyl, cyano or 3- to 6-memberedcarbocycle or heterocycle; or 3- to 6-membered carbocycle orheterocycle; wherein each 3- to 6-membered carbocycle or heterocycle inR_(B) or R_(B)′ is independently optionally substituted at eachoccurrence with one or more substituents selected from halogen, hydroxy,mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo,formyl, cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl,C₂-C₆haloalkenyl or C₂-C₆haloalkynyl; R_(C) is independently selected ateach occurrence from hydrogen, halogen, hydroxy, mercapto, amino,carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; orC₁-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is independentlyoptionally substituted at each occurrence with one or more substituentsselected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,phosphonoxy, phosphono, thioxo, formyl, cyano or 3- to 6-memberedcarbocycle or heterocycle; or 3- to 6-membered carbocycle orheterocycle; wherein each 3- to 6-membered carbocycle or heterocycle inR_(C) is independently optionally substituted at each occurrence withone or more substituents selected from halogen, hydroxy, mercapto,amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl,cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl,C₂-C₆haloalkenyl or C₂-C₆haloalkynyl; R_(E) is independently selected ateach occurrence from —O—R_(S), —S—R_(S), —C(O)R_(S), —OC(O)R_(S),—C(O)OR_(S), —N(R_(S)R_(S)′), —S(O)R_(S), —SO₂R_(S),—C(O)N(R_(S)R_(S)′), —N(R_(S))C(O)R_(S)′, —N(R_(S))C(O)N(R_(S)′R_(S)″),—N(R_(S))SO₂R_(S)′, —SO₂N(R_(S)R_(S)′), —N(R_(S))SO₂N(R_(S)′R_(S)″),—N(R_(S))S(O)N(R_(S)′R_(S)″), —OS(O)—R_(S), —OS(O)₂—R_(S), —S(O)₂OR_(S),—S(O)OR_(S), —OC(O)OR_(S), —N(R_(S))C(O)OR_(S)′, —OC(O)N(R_(S)R_(S)′),—N(R_(S))S(O)—R_(S)′, —S(O)N(R_(S)R_(S)′), —P(O)(OR_(S))₂,═C(R_(S)R_(S)′), or —C(O)N(R_(S))C(O)—R_(S)′; or C₁-C₆alkyl,C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is independently optionallysubstituted at each occurrence with one or more substituents selectedfrom halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,phosphonoxy, phosphono, thioxo, formyl or cyano; or C₃-C₁₂carbocycle, 3-to 12-membered heterocycle or 7- to 12-membered carbocycle orheterocycle, each of which is independently optionally substituted ateach occurrence with one or more substituents selected from (1) halogen,hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,thioxo, formyl, cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, —C(O)OR_(S), or—N(R_(S)R_(S)′), or (2) trimethylsilyl, —O—R_(S), —S—R_(S) or—C(O)R_(S); R_(F) is independently selected at each occurrence fromC₁-C₁₀alkyl, C₂-C₁₀alkenyl or C₂-C₁₀alkynyl, each of which contains 0,1, 2, 3, 4 or 5 heteroatoms selected from O, S or N and is optionallysubstituted with one or more R_(L); or—(R_(X)—R_(Y))_(Q)—(R_(X)—R_(Y)′), wherein Q is 0, 1, 2, 3 or 4, andeach R_(X) is independently O, S or N(R_(B)), wherein each R_(Y) isindependently C₁-C₆alkylene, C₂-C₆alkenylene or C₂-C₆alkynylene each ofwhich is independently optionally substituted with one or moresubstituents selected from halogen, hydroxy, mercapto, amino, carboxy,nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano, and whereineach R_(Y)′ is independently C₁-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyleach of which is independently optionally substituted with one or moresubstituents selected from halogen, hydroxy, mercapto, amino, carboxy,nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; R_(L) isindependently selected at each occurrence from halogen, nitro, oxo,phosphonoxy, phosphono, thioxo, cyano, —O—R_(S), —S—R_(S), —C(O)R_(S),—OC(O)R_(S), —C(O)OR_(S), —N(R_(S)R_(S)′), —S(O)R_(S), —SO₂R_(S),—C(O)N(R_(S)R_(S)′) or —N(R_(S))C(O)R_(S)′; or C₃-C₆carbocycle or 3- to6-membered heterocycle, each of which is independently optionallysubstituted at each occurrence with one or more substituents selectedfrom halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,phosphonoxy, phosphono, thioxo, formyl, cyano, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₁-C₆haloalkyl, C₂-C₆haloalkenyl or C₂-C₆haloalkynyl;wherein two adjacent R_(L), taken together with the atoms to which theyare attached and any atoms between the atoms to which they are attached,can optionally form carbocycle or heterocycle; L_(S), L_(S)′ and L_(S)″are each independently selected at each occurrence from bond; orC₁-C₆alkylene, C₂-C₆alkenylene or C₂-C₆alkynylene, each of which isindependently optionally substituted at each occurrence with one or moreR_(L); and R_(S), R_(S)′ and R_(S)″ are each independently selected ateach occurrence from hydrogen; C₁-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl,each of which is independently optionally substituted at each occurrencewith one or more substituents selected from halogen, hydroxy, mercapto,amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl,cyano, —O—C₁-C₆alkyl, —O—C₁-C₆alkylene—O—C₁-C₆alkyl, or 3- to 6-memberedcarbocycle or heterocycle; or 3- to 6-membered carbocycle orheterocycle; wherein each 3- to 6-membered carbocycle or heterocycle inR_(S), R_(S)′ or R_(S)′ is independently optionally substituted at eachoccurrence with one or more substituents selected from halogen, hydroxy,mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo,formyl, cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl,C₂-C₆haloalkenyl or C₂-C₆haloalkynyl.
 3. The compound or salt accordingto claim 2, wherein J is 3- to 6-membered heterocycle, and is optionallysubstituted with one or more R_(A).
 4. A pharmaceutical compositioncomprising a compound or salt according to claim
 1. 5. A method oftreating HCV infection, comprising administering to an HCV patient acompound or salt according to claim
 1. 6. A process of making a compoundof the invention, comprising a step described in one of the Schemes,General Procedures or Examples described herein.
 7. An intermediatedescribed in one of Schemes, General Procedures or Examples describedherein.
 8. A compound of Formula (a), or a pharmaceutically acceptablesalt thereof:

wherein: A is independently selected from the group consisting of: aryl,heteroaryl, heterocyclic, C₃-C₈ cycloalkyl, and C₃-C₈ cycloalkenyl, alloptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, cyano, —R¹⁰, —R¹¹, —OR¹¹,—N(R¹¹)₂, —C(O)R¹¹, —CO₂R¹¹, C(O)N(R¹¹)₂ and —N(R¹¹)C(O)R¹¹; preferably,A is substituted with -L₃-D described in the specification; R¹⁰ at eachoccurrence is independently C₁-C₄ alkyl optionally substituted with oneor more halogen atoms; R¹¹ at each occurrence is independently hydrogenor optionally substituted C₁-C₈ alkyl; R¹ and R² at each occurrence areeach independently selected from the group consisting of: hydrogen,halogen, cyano, optionally substituted C₁-C₄ alkyl, —O—R¹¹,—NR^(a)R^(b), —C(O)R¹¹, —CO₂R¹¹, and —C(O)NR^(a)R^(b); alternatively, R¹and R² at each occurrence are each independently selected from the groupconsisting of: hydrogen, halogen, cyano, optionally substituted C₁-C₄alkyl, —O—R¹¹, —NR^(a)R^(b), —C(O)R¹¹, —CO₂R¹¹, and —C(O)NR^(a)R^(b);R^(a) and R^(b) at each occurrence are each independently hydrogen,optionally substituted C₁-C₈ alkyl, or optionally substituted C₂-C₈alkenyl; or R^(a) and R^(b) taken together with the nitrogen atom towhich they are attached form an optionally substituted heterocyclic oroptionally substituted heteroaryl group; u and v at each occurrence areeach independently 0, 1, 2, or 3; Q and J are each independentlyselected from:

wherein: R³ and R⁴ at each occurrence are each independently hydrogen,optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈ alkenylor optionally substituted C₃-C₈ cycloalkyl; or alternatively, R³ and R⁴taken together with the carbon atom to which they are attached formoptionally substituted C₃-C₈ cycloalkyl or optionally substitutedheterocyclic; R⁵ at each occurrence is independently hydrogen,optionally substituted C₁-C₈ alkyl, or optionally substituted C₃-C₈cycloalkyl; R⁶ at each occurrence is independently selected from thegroup consisting of: hydrogen, —C(O)—R¹², —C(O)—C(O)—R¹², —S(O)₂—R¹²,and —C(S)—R¹²; R¹² at each occurrence is independently selected from thegroup consisting of: —O—R¹¹, NR^(a)R^(b), —R¹³, —NR^(c)R^(d),—CH(R¹³)NR^(a)R^(b), and —CH(R¹³)NR^(c)R^(d); R¹³ at each occurrence isindependently selected from the group consisting of: optionallysubstituted C₁-C₈ alkyl, optionally substituted C₂-C₈ alkenyl,optionally substituted C₂-C₈ alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally substituted C₃-C₈ cycloalkenyl, optionallysubstituted heterocyclic, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted arylalkyl, and optionallysubstituted heteroarylalkyl; R^(c) and R^(d) at each occurrence are eachindependently selected from the group consisting of: hydrogen, —R¹³,—C(O)—R¹³, —C(O)—OR¹³, —S(O)₂—R¹³, —C(O)N(R¹³)₂, and —S(O)₂N(R¹³)₂; m is0, 1, or 2; n is 0, 1, 2, 3, or 4; X at each occurrence is independentlyselected from O, S, S(O), SO₂, CH₂, CHR⁷, and C(R⁷)₂; provided that whenm is 0, X is selected from CH₂, CHR⁷, and C(R⁷)₂; or R⁷ at eachoccurrence is independently selected from the group consisting of:halogen, cyano, —O—R¹¹, —NR^(a)R^(b), optionally substituted aryl,optionally substituted heteroaryl, and optionally substituted —C₁-C₄alkyl; or, two vicinal R⁷ groups are taken together with the twoadjacent atoms to which they are attached form a fused, optionallysubstituted -C₃-C₈ cycloalkyl or optionally substituted heterocyclicring; or alternatively, two geminal R⁷ groups are taken together withthe carbon atom to which they are attached form a spiro, optionallysubstituted C₃-C₈ cycloalkyl or optionally substituted heterocyclicring,
 9. A compound of claim 8, wherein A is independently a5-7-membered heterocyclic, optionally substituted with one or moresubstituents independently selected from halogen and R₁₀; or apharmaceutically acceptable salt thereof.
 10. A compound of claim 8,wherein u and v at each occurrence are each independently 0 or I; andwhen present, R¹ and R² at each occurrence are each independentlyhalogen or optionally substituted C₁-C₄ alkyl; or a pharmaceuticallyacceptable salt thereof.
 11. A compound of claim 8 wherein Q and J ateach occurrence are each independently selected from:

wherein X at each occurrence is independently CH₂, CF₂, CHF, or CH(OH);or a pharmaceutically acceptable salt thereof.
 12. A compound of claim 8wherein Q and J at each occurrence are each independently

wherein X is CH₂; or a pharmaceutically acceptable salt thereof.
 13. Aprocess of making a compound according to claim 8 comprising the stepsof: i) preparing a compound of Formula (α-a):

via a transition-metal catalyzed cross-coupling reaction; wherein: A, n,u, v, R¹, R², and R⁷ are as defined in claim 23; Z^(a) and Z^(b) areeach independently an amino protecting group or —C(O)—R¹²; R¹² is C₁-C₈alkyl optionally substituted with amino, hydroxy, protected amino, orO(C₁-C₄ alkyl); ii) When Z^(a) or Z^(b) is an amino protecting group,fully or selectively deprotecting a compound of Formula (α-a) to givethe corresponding amine of Formula (α-b):

wherein Z^(c) is hydrogen, an amino protecting group or —C(O)—R¹²; iii)Capping the released amino group of a compound of Formula (α-b) withLG-C(O)—R¹², wherein LG is a leaving group; to give the compound ofFormula (α-c):

wherein Z^(d) is an amino protecting group —C(O)—R¹²; and iv) Repeatedreaction sequence of deprotecting and capping (step ii-iii) to give thecompound of Formula (α-d):


14. A compound of Formula (β) or pharmaceutically acceptable saltsthereof:

wherein: A is a cyclic group independently selected from aryl,heteroaryl, heterocyclic, C₃-C₈ cycloalkyl, and C₃-C₈ cycloalkenyl, eachoptionally substituted; preferably A is substituted with -L₃-D describedin the specification; D is absent or an optionally substituted aliphaticgroup; T is absent or an optionally substituted linear aliphatic groupcontaining zero to eight carbons; E is absent or independently selectedfrom optionally substituted aryl and optionally substituted heteroaryl;wherein at least one or two of D, E, and T are absent; R¹ and R² at eachoccurrence are each independently selected from the group consisting ofhydrogen, halogen, cyano, optionally substituted C₁-C₄ alkyl,—O—R¹¹,—NR^(a)R^(b), —C(O)R¹¹, —CO₂R¹¹, and —C(O)NR^(a)R^(b); R¹¹ ateach occurrence is independently hydrogen or optionally substitutedC₁-C₈ alkyl; R^(a) and R^(b) at each occurrence are each independentlyselected from the group consisting of hydrogen, optionally substitutedC₁-C₈ alkyl, and optionally substituted C₂-C₈ alkenyl; or R^(a) andR^(b) can be taken together with the nitrogen atom to which they areattached to form an optionally substituted heterocyclic or optionallysubstituted heteroaryl group; u and v at each occurrence are eachindependently 1, 2, or 3; Q and J are each independently selected from:

R³ and R⁴ at each occurrence are each independently selected from thegroup consisting of hydrogen, optionally substituted C₁-C₈ alkyl,optionally substituted C₂-C₈ alkenyl, and optionally substituted C₃-C₈cycloalkyl; or alternatively, R³ and R⁴ can be taken together with thecarbon atom to which they are attached to form optionally substitutedC₃-C₈ cycloalkyl or optionally substituted heterocyclic; R⁵ at eachoccurrence is independently hydrogen, optionally substituted C₁-C₈alkyl, or optionally substituted C₃-C₈ cycloalkyl; R⁶ at each occurrenceis independently selected from the group consisting of —C(O)—R¹²,—C(O)—C(O)—R¹², —S(O)₂—R¹², and —C(S)—R¹²; R¹² at each occurrence isindependently selected from the group consisting of: —O—R¹¹,—NR^(c)R^(d); —R¹³, and —NR^(a)R^(b); R¹³ at each occurrence isindependently selected from the group consisting of hydrogen, C₁-C₈alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₃-C₈cycloalkenyl, heterocyclic, aryl, and heteroaryl, each optionallysubstituted; or R^(c) and R^(d) at each occurrence are eachindependently selected from the group consisting of hydrogen, —R¹³,—C(O)—R¹³, —C(O)—OR¹³, —S(O)₂—R¹³, —C(O)N(R13)₂, and —S(O)₂N(R¹³)₂; m is0, 1, or 2; n is 1, 2, 3, or 4; X at each occurrence is independentlyselected from O, S, S(O), SO₂, and C(R⁷)₂, provided that when m is 0, Xis C(R⁷)₂; and R⁷ at each occurrence is independently selected from thegroup consisting of hydrogen, halogen, —C₁-C₄ alkyl, cyano, —O—R¹¹,—NR^(a)R^(b), optionally substituted aryl, optionally substitutedheteroaryl, and optionally substituted with —C₁-C₄ alkyl; or two vicinalR⁷ groups can be taken together with the two adjacent atoms to whichthey are attached to form a fused, optionally substituted C₃-C₈cycloalkyl or optionally substituted heterocyclic ring; or alternativelytwo geminal R⁷ groups can be taken together with the carbon atom towhich they are attached to form a spiro, optionally substituted C₃-C₈cycloalkyl or optionally substituted heterocyclic ring;
 15. The compoundof claim 14, wherein Q and J are each independently selected from:

wherein X is independently CH₂, CF₂, CHF, or CH(OH); or apharmaceutically acceptable salt thereof.
 16. The compound of claim 14,wherein Q and J are each independently

and R¹ and R² are each hydrogen; or a pharmaceutically acceptable saltthereof.
 17. The compound of claim 16, wherein D and E are absent; or apharmaceutical acceptable salt thereof.
 18. A process of making acompound according to claim 14 wherein D and E are absent, comprisingthe steps of: i) preparing a compound of Formula (β-a):

via a transition-metal catalyzed cross-coupling reaction; amide or ureaformation; ester or carbamate formation; or ether formation; wherein: A,T, n, u, v, R¹, R², and R⁷ are as defined in claim 29; Z^(a) and Z^(b)are each independently an amino protecting group or —C(O)—R¹²; R¹² isC₁-C₈ alkyl optionally substituted with amino, hydroxy, protected amino,or O(C₁-C₄ alkyl); ii) When Z^(a) or Z^(b) is an amino protecting group,fully or selectively deprotecting a compound of Formula (β-a) to givethe corresponding amine of Formula (β-b):

wherein Z^(c) is hydrogen, an amino protecting group or —C(O)—R¹²; iii)Capping the released amino group of a compound of Formula (β-b) withLG-C(O)—R¹², wherein LG is a leaving group; to give the compound ofFormula ((β-c):

wherein Z^(d) is an amino protecting group —C(O)—R¹²; and iv) Repeatedreaction sequence of deprotecting and capping (step ii-iii) to give thecompound of Formula ((β-d):


19. A compound of Formula (γ) or a pharmaceutically acceptable saltthereof:

A and A′ are independently selected from the group consisting of asingle bond, —(CR₂)_(n)—C(O)—(CR₂)_(p)—, —(CR₂)_(n)O—(CR₂)_(p)—,—(CR₂)_(n)—N(R^(N))—(CR₂)_(p)—, —(CR₂)_(n)—S(O)_(k)—N(R^(N))—(CR₂)_(p)—,—(CR₂)_(n)—C(O)—N(R^(N))—(CR₂)_(p)—,—(CR₂)_(n)—N(R^(N))—C(O)—N(R^(N))—(CR₂)_(n)—,—(CR₂)_(n)—C(O)—O—(CR₂)_(p)—,—(CR₂)_(n)—N(R^(N))—S(O)_(k)—N(R^(N))—(CR₂)_(p)— and—(CR₂)_(n)—N(R^(N))—C(O)—O—(CR₂)_(p)— and a heteroaryl group selectedfrom the group consisting of

wherein: X¹ is CH₂, NH, O or S, Y¹, Y² and Z¹ are each independently CHor N, X² is NH, O or S, V is —CH₂—CH₂—, —CH═CH—, —N═CH—,(CH₂)_(a)—N(R^(N))—(CH₂)_(b)— or —(CH₂)_(a)—O—(CH₂)_(b)—, wherein a andb are independently 0, 1, 2, or 3 with the proviso that a and b are notboth 0,

optionally includes 1 or 2 nitrogens as heteroatoms on the phenylresidue, the carbons of the heteroaryl group are each independentlyoptionally substituted with a substituent selected from the groupconsisting of —OH, —CN, —NO₂, halogen, C₁-C₁₂ alkyl, C₁-C₁₂ heteroalkyl,cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy,alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate,sulfonamide and amino, the nitrogens, if present, of the heteroarylgroup are each independently optionally substituted with a substituentselected from the group consisting of —OH, C₁ to C₁₂ alkyl, C₁ to C₁₂heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy,alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate andsulfonamide, a and b are independently 1, 2, or
 3. c and d areindependently 1 or 2, n and p are independently 0, 1, 2 or 3, k is 0, 1,or 2, each R is independently selected from the group consisting ofhydrogen, —OH, —CN, —NO₂, halogen, C₁ to C₁₂ alkyl, C₁ to C₁₂heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy,alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate,sulfonamide and amino, each R^(N) is independently selected from thegroup consisting of hydrogen, —OH, C₁ to C₁₂ alkyl, C₁ to C₁₂heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy,alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate andsulfonamide, and wherein for each A and A′, B may be attached to eitherside of A and A′ so that in the example of A or A′ being

the A-B-A′ can be any of:

B is Q or Q-Q, wherein each Q is independently selected from the groupconsisting of a cycloalkyl group, cycloalkenyl group, heterocycle, arylgroup or heteroaryl group, with the proviso that only one Q is a sixmember aromatic ring when B is Q-Q, and/or with the proviso that if B isQ-Q, any Q is that is polycyclic is connected to the remainder of themolecule through only one cycle of the polycycle; preferably, B issubstituted with -L₃-D described in the specification; R^(c), R^(d),R^(e) and R^(f) are each independently selected from the groupconsisting of: hydrogen, C₁ to C₈ alkyl, C₁ to C₈ heteroalkyl, aralkyland a 4- to 8-membered ring which may be cycloalkyl, heterocycle,heteroaryl or aryl, wherein, each heteroatom, if present, isindependently N, O or S, each of R^(c), R^(d), R^(e) and R^(f) mayoptionally be substituted by C₁-C₈ alkyl, C₁ to C₈ heteroalkyl, aralkyl,or a 4- to 8-membered ring which may be cycloalkyl, heterocycle,heteroaryl or aryl and wherein each heteroatom, if present, isindependently N, O or S, R^(c) and R^(d) are optionally joined to form a4- to 8-membered heterocycle which is optionally fused to another 3- to6-membered heterocycle or heteroaryl ring, and R^(e) and R^(f) areoptionally joined to form a 4- to 8-membered heterocycle which isoptionally fused to another 3- to 6-membered heterocycle or heteroarylring; Y and Y′ are each independently carbon or nitrogen; and Z and Z′are independently selected from the group consisting of hydrogen, C₁ toC₈ alkyl, C₁ to C₈ heteroalkyl, cycloalkyl, heterocycle, aryl,heteroaryl, aralkyl, 1-3 amino acids, —[U—(CR⁴ ₂)₁—NR⁵—(CR⁴₂)_(t)]_(u)—U—(CR⁴ ₂)_(t)—NR⁷—(CR⁴ ₂)_(t)—R⁸, —U—(CR⁴ ₂)_(t)—R⁸ and—[U—(CR⁴ ₂)_(t)—NR⁵—(CR⁴ ₂)_(t)]_(u)—U—(CR⁴ ₂)_(t)—O—(CR⁴ ₂)_(t)—R⁸,wherein, U is selected from the group consisting of —C(O)—, —C(S)— and—S(O)₂—, each R⁴, R⁵ and R⁷ is independently selected from the groupconsisting of hydrogen, C₁ to C₈ alkyl, C₁ to C₈ heteroalkyl,cycloalkyl, heterocycle, aryl, heteroaryl and aralkyl, R⁸ is selectedfrom the group consisting of hydrogen, C₁ to C₈ alkyl, C₁ to C₈heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl,—C(O)—R⁸¹, —C(S)—R⁸¹, —C(O)—O—R⁸¹, —C(O)—N—R⁸¹, —S(O)₂—R⁸¹ and—S(O)₂—N—R⁸¹ ₂, wherein each R⁸¹ is independently chosen from the groupconsisting of hydrogen, C₁ to C₈ alkyl, C₁ to C₈ heteroalkyl,cycloalkyl, heterocycle, aryl, heteroaryl and aralkyl, optionally, R⁷and R⁸ together form a 4-7 membered ring, each t is independently 0, 1,2, 3, or 4, and u is 0, 1, or
 2. 20. The compound of claim 19 whereineach Q is independently optionally substituted with one or moresubstituents each independently selected from the group consisting of—OH, —CN, —NO₂, halogen, C₁ to C₁₂ alkyl, C₁ to C₁₂ heteroalkyl,cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy,alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate,sulfonamide and amino, and if Q is not aromatic, it is optionallysubstituted with oxo.
 21. The compound of claim 20 wherein each Q isindependently optionally substituted with —CN, —OCF₃, —OCHF₂, —CF₃, or—F.
 22. The compound of claim 21 wherein A and A′ are independentlyselected from the group consisting of a single bond,—(CR₂)_(n)—O—(CR₂)_(p)—, —(CR₂)_(n)—N(R^(N))—(CR₂)_(p)—,—(CR₂)_(n)—C(O)—N(R^(N))—(CR₂)_(p)—,—(CR₂)_(n)—N(R^(N))—C(O)—N(R^(N))—(CR₂)_(p)—, and—(CR₂)_(n)—N(R^(N))—C(O)—O—(CR₂)_(p)— and a heteroaryl group selectedfrom the group consisting


23. The compound of claim 22 wherein A and A′ are independently selectedfrom the group consisting of a single bond,


24. The compound of claim 22 wherein one or both of R^(c) and R^(d) orR^(e) and R^(f) are joined to form a 4- to 8-membered heterocycle whichis optionally fused to another 3- to 6-membered heterocycle.
 25. Thecompound of claim 22 wherein R^(c) and R^(d) are joined to form

and R^(e) and R^(f) are joined to form


26. The compound of claim 25, wherein one or both of Z and Z′ are—C(O)—(CR⁴ ₂)_(n)—NR⁷—C(O)—O—R⁸¹.
 27. A compound of Formula (δ) orpharmaceutically acceptable salts thereof:

A and A′ are independently selected from the group consisting of asingle bond, —(CR₂)_(n)—C(O)—(CR₂)_(p)—, —(CR₂)_(n)—O—(CR₂)_(p)—,—(CR₂)_(n)N(R^(N))—(CR₂)_(p), —(CR₂)_(n)—S(O)_(k)—(CR₂)_(p)—,—(CR₂)_(n)—S(O)_(k)—N(R^(N))—(CR₂)_(p)—,—(CR₂)_(n)—C(O)—N(R^(N))—(CR₂)_(p)—,—(CR²)_(n)—N(R^(N))—C(O)—N(R^(N))—(CR₂)_(p),—(CR₂)_(n)—C(O)—O—(CR²)_(p)—,—(CR₂)_(n)—N(R^(N))—S(O)_(k)—N(R^(N))—(CR₂)_(p)— and—(CR₂)_(n)—N(R^(N))—C(O)—O—(CR₂)_(p)— and a heteroaryl group selectedfrom the group consisting of

wherein: X¹ is CH₂, NH, O or S, Y¹, Y² and Z¹ are each independently CHor N, X² is NH, O or S, V is —CH₂—CH₂—, —CH═CH—, —N═CH—,(CH₂)_(a)—N(R^(N))—(CH₂)_(b)— or —(CH₂)_(a)—O—(CH₂)_(b)—, wherein a andb are independently 0, 1, 2 or 3 with the proviso that a and b are notboth 0,

optionally includes 1 or 2 nitrogens as heteroatoms on the phenylresidue, the carbons of the heteroaryl group are each independentlyoptionally substituted with a substituent selected from the groupconsisting of —OH, —CN, —NO₂, halogen, C₁ to C₁₂ alkyl, C₁ to C₁₂heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy,alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate,sulfonamide and amino, the nitrogens, if present, of the heteroarylgroup are each independently optionally substituted with a substituentselected from the group consisting of —OH, C₁ to C₁₂ alkyl, C₁ to C₁₂heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy,alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate andsulfonamide, a and b are independently 1, 2 or
 3. c and d areindependently 1 or 2, n and p are independently 0, 1, 2 or 3, k is 0, 1or 2, each R is independently selected from the group consisting ofhydrogen, —OH, —CN, —NO₂, halogen, C₁ to C₁₂ alkyl, C₁ to C₁₂heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy,alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate,sulfonamide and amino, each R^(N) is independently selected from thegroup consisting of hydrogen, —OH, C₁ to C₁₂ alkyl, C₁ to C₁₂heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy,alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate andsulfonamide, wherein for each A and A′, B may be attached to either sideof A and A′ so that in the example of A or A′ being,

the A-B-A′ can be any of:

and wherein only one of A and A′ is a 5-membered heteroaryl ring if B isW—W; B is W—W or W—X″—W; wherein each W is an aryl group or a heteroarylgroup, and X″ is selected from the group consisting of —O—, —S(O)_(k),—N(R^(N))— and —CR′₂—, preferably B is substituted with -L₃-D describedin the specification; each R′ is independently selected from the groupconsisting of hydrogen, —OH, —CN, C₁ to C₁₂ alkyl, C₁ to C₁₂heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy,alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate,sulfonamide and amino and the two R′ are optionally joined to form a 3-to 8-membered ring, and each W is independently optionally substitutedwith one or more substituents each independently selected from the groupconsisting of —OH, —CN, —NO₂, halogen, C₁ to C₁₂ alkyl, C₁ to C₁₂heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy,alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate,sulfonamide and amino; R^(c), R^(d), R^(e) and R^(f) are eachindependently selected from the group consisting of: hydrogen, C₁ to C₈alkyl, C₁ to C₈ heteroalkyl, aralkyl and a 4- to 8-membered ring whichmay be cycloalkyl, heterocycle, heteroaryl or aryl, wherein, each heteroatom, if present, is independently N, O or S, each of R^(c), R^(d),R^(e) and R^(f) may optionally be substituted by C₁ to C₈ alkyl, C₁ toC₈ heteroalkyl, aralkyl or a 4- to 8-membered ring which may becycloalkyl, heterocycle, heteroaryl or aryl and wherein each heteroatom,if present, is independently N, O or S, R^(c) and R^(d) are optionallyjoined to form a 4- to 8-membered heterocycle which is optionally fusedto another 3- to 6-membered heterocycle or heteroaryl ring, and R^(e)and R^(f) are optionally joined to form a 4- to 8-membered heterocyclewhich is optionally fused to another 3- to 6-membered heterocycle orheteroaryl ring; Y and Y′ are independently carbon or nitrogen; and Zand Z′ are independently selected from the group consisting of hydrogen,C₁ to C₈ alkyl, C₁ to C₈ heteroalkyl, cycloalkyl, heterocycle, aryl,heteroaryl, aralkyl, 1-3 amino acids, —[U—(CR⁴ ₂)_(t)—NR⁵—(CR⁴₂)_(t)]_(u)—U—(CR⁴ ₂)_(t)—NR⁷—(CR⁴ ₂)_(t)—R⁸, —U—(CR⁴ ₂)_(t)—R⁸ and—[U—(CR⁴ ₂)_(t)—NR⁵—(CR⁴ ₂)_(t)]_(u)—U—(CR⁴ ₂)_(t)—O—(CR⁴ ₂)_(t)—R⁸,wherein, U is selected from the group consisting of —C(O)—, —C(S)— and—S(O)₂—, each R⁴, R⁵ and R⁷ is independently selected from the groupconsisting of hydrogen, C₁ to C₈ alkyl, C₁ to C₈ heteroalkyl,cycloalkyl, heterocycle, aryl, heteroaryl and aralkyl, R⁸ is selectedfrom the group consisting of hydrogen, C₁ to C₈ alkyl, C₁ to C₈heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl,—C(O)—R⁸¹, —C(S)—R⁸¹, —C(O)—O—R⁸¹, —C(O)—N—R⁸¹ ₂, —S(O)₂—R⁸¹ and—S(O)₂—N—R⁸¹ ₂, wherein each R⁸¹ is independently chosen from the groupconsisting of hydrogen, C₁ to C₈ alkyl, C₁ to C₈ heteroalkyl,cycloalkyl, heterocycle, aryl, heteroaryl and aralkyl, optionally, R⁷and R⁸ together form a 4-7 membered ring, each t is independently 0, 1,2, 3 or 4, and u is 0, 1 or 2,
 28. The compound of claim 27, wherein Bis W—W.
 29. The compound of claim 28 wherein A is selected from(CR₂)_(n)—O—(CR₂)_(p)—, —(CR₂)_(n)—C(O)—N(R^(N))—(CR₂)_(p)—.
 30. Thecompound of claim 28 wherein A′ is selected from the group consistingof:


31. The compound of claim 29 wherein one or both of R^(c) and R^(d) orR^(e) and R^(f) are joined to form a 4- to 8-membered heterocycle whichis optionally fused to another 3- to 6-membered heterocycle.
 32. Thecompound of claim 30 wherein one or both of R^(c) and R^(d) or R^(e) andR^(f) are joined to form a 4- to 8-membered heterocycle which isoptionally fused to another 3- to 6-membered heterocycle.
 33. Thecompound of claim 29 wherein R^(c) and R^(d) are joined to form

and R^(e) and R^(f) are joined to form


34. The compound of claim 30 wherein R^(c) and R^(d) are joined to form

and R^(e) and R^(f) are joined to form


35. The compound of claim 33, wherein one or both of Z and Z′ are—C(O)—(CR⁴ ₂)_(n)—NR⁷—C(O)—O—R⁸¹.
 36. The compound of claim 34, whereinone or both of Z and Z′ are —C(O)—(CR⁴ ₂)_(n)—NR⁷—C(O)—O—R⁸.